Cichorium glandulosum Boiss. et Huet is a genus of chicory in the family of Asteraceae, and it is a “medicine food homology” herbal medicine, which has the effect of detoxifying heat, diuretic and swelling, and strengthening the stomach. This paper reviews the chemical composition, pharmacological effects, and practical applications of Cichorium glandulosum Boiss. et Huet and provides a comprehensive account of its role in human health and diet, pharmacological activities, and toxicity. Cichorium glandulosum Boiss. et Huet, “medicine food homology” herbal medicine, is often widely used in compound formulations with functions such as clearing the liver, promoting gallbladder, and enhancing immunity. Previous studies have found that multiple chemical components have been isolated and identified from Cichorium glandulosum Boiss. et Huet, mainly including 89 compounds such as flavonoids, terpenoids, phenolic acids, polysaccharides, and phenylpropanoids. Meanwhile, the extract has various biological activities, including hepatoprotective and hypoglycemic, regulating blood lipids, aiding digestion, anticancer, regulating intestinal microbiota and immune function, antioxidant, and has been proven in both in vivo and in vitro studies. As an important plant resource, the current research focuses on the traditional efficacy of Cichorium glandulosum Boiss. et Huet. The chemical composition of this genus of plants is complex and their pharmacological activities are diverse. Further in-depth studies on the molecular mechanisms and toxic side effects of its specific compounds in the organism are needed. Therefore, this review provides a reference for the development and utilization of Cichorium glandulosum Boiss. et Huet.
This review presents traditional formulations, chemical composition, pharmacology, and toxicology of Cichorium glandulosum Boiss. et Huet.
Phytochemistry of Cichorium glandulosum Boiss. et Huet is dominated by Flavonoids, Terpenoids, and Phenylpropanoids compounds.
Polyherbal formulations studies on Cichorium glandulosum Boiss. et Huet are discussed.
The pharmacological aspect of extracts and pure compounds is comprehensively discussed in detail.
Introduction
Cichorium glandulosum Boiss. et Huet is Cichorium of Compositae, and it is a variety herb of Cichorium in Xinjiang. Its traditional Chinese medicine (TCM) names are Cichorium intybus L, chicory, bitter chrysanthemum, blue chrysanthemum, coffee grass, and others. Its active ingredients include terpenoids, flavonoids, phenylpropanoids, phenolic acids, polysaccharides, and others. According to the Xinjiang Chinese Herbal Medicine Manual,1 chicory has the following effects: clearing heat and detoxification, diuresis, detumescence, and stomach strengthening. The plant is resistant to cold and drought and mainly grows in coastal wasteland, riverside, hillside, and other places. It is distributed in the central and northeast parts of Xinjiang, China. It is also widely distributed in Europe, Asia, and North Africa. The Pharmacopoeia of the People's Republic of China Volume 1 of 2020 includes chicory and dry aboveground parts and roots of Cichorium glandulosum Boiss. et Huet as Chinese herbal medicine chicory.2 In the summer and autumn, its aboveground parts are used, or its roots are dug at the end of autumn. The sediment and impurities are removed, and the plant parts are dried for use as medicine.
Cichorium glandulosum Boiss. et Huet is a dual-purpose plant used for medicine and food. Its leaves are tender and juicy and rich in various amino acids and trace elements, especially starch, vitamins, calcium, which contribute to the acceptable taste, and it has high utilization rate and rich in nutrients.3–6 It can be used to prepare lettuce stir fry and to make snacks. It can also be used with balsam pear and ribs to make soup. It can relieve heat, thirst, and blood pressure.7,8 Its roots contain inulin and aromatic substances. In Europe, America, and other countries, the fleshy roots of chicory are processed to produce substitute coffee or additives.9 Inulin can also be used in chocolate products instead of cream. It will not cause dental caries, can prevent constipation, and can reduce the risk of cancer.10 In this paper, “Cichorium glandulosum Boiss. et Huet” and “chicory” are used as keywords to search the Web of Science, PubMed, CNKI, SinoMed, Wanfang, Weipu, Baidu Scholar and other literature databases, and systematically reviews the chemical composition, pharmacological effects, and practical applications of Cichorium glandulosum Boiss. et Huet, shedding light on its dual roles in human health and diet, as well as its pharmacological activities and potential toxicities. These provide new value and direction for the research, development, and application of Cichorium glandulosum Boiss. et Huet.
Application in Traditional Chinese Medicine and Diet
In China's traditional diet culture, some Chinese medicinal materials are often widely eaten as food in folk medicine. According to the documents issued by the State Health Commission and the State Administration of Market Supervision and Administration, Cichorium glandulosum Boiss. et Huet can be used as both medicine and food within the limited scope of use and dosage. The relevant products developed at present include health drinks represented by chicory weight-reducing tea and snacks related to chicory. These are safe and can be used for health care. They are often loved by people. The plant is a high-quality feed that is rich in extracted nutrients and has high digestibility, utilization rate, and wide application range. It has a long history of being used as food (vegetable) in China, Europe, Italy, and other places.
In the Pharmacopoeia of the People's Republic of China,2 it is recorded that the main therapeutic functions of Cichorium glandulosum Boiss. et Huet include clearing the liver, relieving bile, reducing swelling and diuresis, strengthening the spleen and nourishing the stomach. Based on traditional understanding, Cichorium glandulosum Boiss. et Huet is mainly used to regulate endocrine, enhance immunity, clear liver and gallbladder, strengthen stomach and digestion, diuresis and detumescence. It is commonly seen clinically in the treatment of hepatitis, nephritis, gastric fever, hyperlipidemia, hyperuric acid, gout and various febrile diseases.11 Its health care products and preparations are in various forms, such as granules, oral liquid, pills, and capsules. So far, Cichorium glandulosum Boiss. et Huet has been recognized and applied in China and other countries such as Europe and America. With the in-depth study of chicory as a dual-use medicine and food, its medicinal value for the prevention and treatment of corresponding diseases has been constantly reflected in various TCM prescriptions, including “QingReKaSenKeLi,” “Fufang Muniziqi Keli,” “HuGanBuZuReKeLi,” and “YanXiaoDiNaErTangJiang,” which have been recorded in the “Drug Standards of the Ministry of Health of the People's Republic of China - Uygur Medicine Volume.” The above characteristic compound preparations have diuretic and detumescence effects.11,12 Moreover, the following prescriptions can clear the liver, promote gallbladder, and improve immunity: “Chicory acid (CA) ester clear capsule,”13 “Chicory Shuangjiang Pill,”14 “Chicory and Jujube Oral Liquid,”15 and so on. Nowadays, more and more people prefer to eat foods with medicinal functions rather than take chemical drugs. Therefore, it is necessary to combine the TCM and dietary medicines; Table 1 shows the common herbal formulations containing Cichorium glandulosum Boiss. et Huet and their pharmacological effects.
Classical Prescriptions of Cichorium glandulosum Boiss. et Huet in TCM and Diet.
It helps to reduce protein decomposition and metabolism in the body during exercise and inhibit lactic acid production, thus having a better anti-fatigue function.
Chemical Composition
According to research, the chemical composition of different parts of Cichorium glandulosum Boiss. et Huet contains flavonoids, terpenoids, phenylpropanoids, alkaloids, polysaccharides, organic acids, phytosterols, and others.
Flavonoids
Flavonoids are among the effective components of Cichorium glandulosum Boiss. et Huet, and their biological activities and safety often attract researchers’ attention. In one study, the components in Cichorium glandulosum Boiss. et Huet were separated and purified by column chromatography, and their structures were identified by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. The flavonoids were identified as quercetin, isoquercetin, kaempferol-3-glucuronide, isorhamnetin 3-glucuronide, and quercetin 3-O-β-D-glucuronide. Among these, quercetin 3-O-β-D-glucuronide was firstly obtained from this compound, and the other compounds were first isolated from this plant.16 The 2 red chicory varieties and green chicory were analyzed using HPLC/DAD/MS, and chromatographic fingerprinting was used to diagnose the chromatograms of different varieties. The red variety of chicory contained anthocyanin 3-O-glucoside and anthocyanin 3-O-(6-malonyl) glucoside. Meanwhile, HPLC/DAD/MS analysis identified quercetin and quercetin malonyl glucoside in chicory (76), as well as methyl quercetin malonyl glucoside, kaempferol, lignan, apigenin glucoside, and apigenin-7-O-arabinoside.17–19 One study used chicory to synthesize silver nanoparticles, which were analyzed to show the high content of total phenols and total flavonoids. The high antioxidant activity of silver nanoparticles was also shown by FRAM and 2,2-Diphenyl-1-picrylhydrazyl (DPPH) assays. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry were used to study its anti-cancer activity. The activity and apoptosis of MDA-MB231 cells treated with it were determined. It had potential as an antioxidant and has anti-bacterial and anti-cancer properties.20
Anthocyanidin is a kind of flavonoid, which is widely distributed in plants. It gives different plants unique colors and helps to promote people's appetite. These have antioxidant capacity (AOP) and have certain health functions, such as antioxidant and anti-inflammatory. Anthocyanin 3-O-(6-malonyl)-glucoside accounts for more than 90% of the anthocyanins in the red variety. Thus, Cichorium glandulosum Boiss. et Huet has important health functions.17,21 The flavonoids in Cichorium glandulosum Boiss. et Huet are shown in Table 2 and the compound structure is shown in Figure 1.
Structural formula of flavonoids in Cichorium glandulosum Boiss. et Huet. (Note: 1. The serial numbers in the figure correspond to the serial numbers of the compounds in Table 2 and section “Flavonoids” of the article. 2. Compounds without sequence numbers in Figures 1-4 do not have relevant information.).
Chemical Composition From Cichorium glandulosum Boiss. et Huet.
Terpenoids are an important class of components in herbal medicine with the general formula (C5H8)n. The general name of polymers with isoprene as the basic structural unit and their derivatives. Terpenoids are widely found in nature, and most of them are found in higher plants. Among them, Cichorium glandulosum Boiss. et Huet is also one of the most important active ingredients, mainly sesquiterpenes and triterpenes in Cichorium glandulosum Boiss. et Huet, depending on the number of isoprene units included in the molecule.
Sesquiterpenoids
Sesquiterpenes are a class of compounds containing 3 isoprene units and their derivatives, which are mainly found in plant volatile oils. The sesquiterpenoids of Cichorium glandulosum Boiss. et Huet mostly form lactones. The sesquiterpenoid lactones have the characteristics of Compositae and are the main reason for the bitter taste of chicory plants. These include lactucin, lactucopicrin, and 11β,13-dihydrolactucopicrin, which is the main ingredient that contributes to bitterness, and it is also a characteristic related to the promotion of human and animal appetite and digestion.34,50,51 The compound identified by spectroscopy as 2α,6β,7β,15-tetrahydroxy-1(10),4(5)-diene-guaian-9α,12-olide-7-O-β-caffoyl-15-O-β-D-glucoside was a new sesquiterpene glycoside isolated from the methanol extract of Compositae seeds. Through a study on the toxicity of carbon tetrachloride in Wistar rats, the serum glutamic acid transaminase (SGOT) and other liver enzymes were reduced. The compound had significant anti-hepatotoxic activity.52 Costunolide (Cos) is a sesquiterpene lactone extracted from Cichorium glandulosum Boiss. et Huet. This study activated intrinsic apoptosis and autophagy by Cos, promoting reactive oxygen species (ROS) levels and inhibiting the ROS-AKT/GSK3β signaling pathway. The antitumor activity of Cos was assessed using subcutaneous xenografts of HGC-27 into Balb/c nude mice. Furthermore, intervention of gastric cancer cells with 3-methyladenine (3-MA) cellular autophagy inhibitor showed significant attenuation of Cos-induced apoptosis. This finding suggests that Cos has potential in the treatment of gastric cancer.44 The sesquiterpenoids already present in Cichorium glandulosum Boiss. et Huet are shown in Table 2 and the compound structure is shown in Figure 2.
Structural formula of terpenoids in Cichorium glandulosum Boiss. et Huet. (Note: The sequence numbers in the figure correspond to the compound sequence numbers in Table 2 and section “Triterpenoids” of the article.).
Triterpenoids
According to literature survey, the triterpenoids in Cichorium glandulosum Boiss. et Huet mainly include α-Amyrin (77), baurenyl acetate, Taraxerone (78), β-Sitosterol, Taraxasterol (79), ψ-taraxasterol, and others.32,53,54
First isolation of 2 new triterpene components from the methanolic extract of chicory, characterized as Arabic palmitate lup-12,20(29)-dien-3b-ol-3b-L-arabinofura-nosyl-20-hexadecanoate and palmitate lup-12, 20(29)-dien-3b-olyl hexadecanoate.55 The ethanol extract and supercritical fluid extract of the above-ground part of chicory plant were separated and purified by silica gel column, and the structures of the separated compounds were determined by NMR and mass spectrometry. It was determined that triterpenoids were isolated for the first time 28β-hydroxytaraxasterol and known compounds β-Sitosterol and β-sitosterol-3-O-glucoside.56
Phenylpropanoids
Phenylpropanoid is a benzopyranone compound with insect antifeedant, antiviral, antibacterial, and immunosuppressive effects. Its content accounts for a large proportion in the compounds of chicory, which is of great research significance. Phenylpropanoids were isolated from chicory tissues, and the isolated compounds were characterized by spectroscopic methods. A new natural product was isolated from chicory leaves, and a new coumarin glucoside, cichoriin 6-hydroxyphenylacetate, was obtained.47,57 The common phenylpropanoid compounds in Cichorium glandulosum Boiss. et Huet are shown in Table 2 and the compound structure is shown in Figure 3.
Structural formulas of phenylpropanoids (55-62) and phenolic acid compounds (63-75) in Cichorium glandulosum Boiss. et Huet. (Note: The sequence numbers in the figure correspond to the compound sequence numbers in Table 2.).
Phenolic Acids
Phenolic acids are important effective ingredients in Cichorium glandulosum Boiss. et Huet. Thus, chicory roots can be used as coffee or additives after drying.58 Polyphenols were isolated and identified in various species of the chicory genus using HPLC-PDA-ESI-MSn method, as mentioned in previously published literature. Among the 64 compounds detected, hydroxycinnamic acid derivatives, including 8 monocaffeoyl acids containing dimethylcinnamic oxalic and dicaffeoyl tartaric acids, as well as 3 tartaric acid derivatives were identified based on UV spectra and MSn fragment patterns. For the first time, several isomers of caffeic acid derivatives were distinguished by their specific mass spectrometric data. Based on the analysis of the extraction kinetic model, the conditions were optimized. The obtained ethanolic extracts in the range of 35% to 70% at 40 °C had high antioxidant activity.59,60
Chicoric acid (CA) is the main active component of the phenolic acid class of chicory species. It has renoprotective, anti-inflammatory, viral, and obesity effects. It improves the regulation of LC3, SQSTM1, Mfn2, and FIS1 mitochondrial dynamics gene expressions to reduce mitochondrial damage in renal tubular epithelial cells in obesity-associated chronic kidney disease.61 The inhibitory effect of CA on TLR4/MyD88/NF-κB signaling pathway indicates that CA has neuroprotective effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) in mice. CA may regulate intestinal microbiota and inhibit inflammation of the whole brain gut axis.62 The compounds methyl p-hydroxyphenylacetate and 4-hydroxyphenylacetic acid were isolated and identified from chicory. The results of silica analysis and Western blot showed that methyl p-hydroxyphenylacetate could target Akt-1 in liver cells. 4-Hydroxyphenylacetic acid could reduce the protein expression levels of caspase-1 and Akt-1 simultaneously, thereby improving liver damage to a certain extent. This helps clarify the effect of chicory on liver cells and the mechanism underlying its improvement of liver damage.27 The phenolic acid compounds proved to be contained in Cichorium glandulosum Boiss. et Huet are shown in Table 2 and the compound structure is shown in Figure 3.
Saccharides
Saccharides are a class of carbohydrates, which widely found in nature as 1 of the 4 basic substances that constitute life, such as plant seeds, stems and leaves, animal mucus, and insects. It exerts bioactive effects in anti-inflammatory, anti-viral, anti-tumor, hypoglycemic, and immune promotion. The Cichorium glandulosum Boiss. et Huet mainly contains inulin, sucrose, fructose (80), dextrose (81), and β-D-Fructofuranose (82), of which inulin accounts for the largest proportion.63–66
Inulin and oligofructose are fructans composed of linear chains of β(2→1) fructose monomers. Inulin in Cichorium glandulosum Boiss. et Huet is an important reserve polysaccharide in the Asteraceae family, and is a source of sweetener, dietary fiber and prebiotics, which has often led to extensive research on the metabolism and regulation of inulin by researchers.67–69 Chicory fresh root (chicory) is the main industrial source of inulin and oligofructose.70 Inulin and oligofructose intake can enhance the absorption of minerals such as calcium, magnesium, and iron in the gastrointestinal tract.71 Different degrees of fructan polymerization can affect some product characteristics, such as digestibility, caloric value, sweetness ability, and others.72 The results showed that CIP70-1, an inulin fructan isolated from chicory, showed weak anti-tumor activity.73 In addition, inulin also exhibits excellent health benefits in glycolipid metabolism, inhibiting the expression of inflammatory factors, enhancing mineral absorption, and improving constipation.74 The structure of related polysaccharide compounds is shown in Figure 4.
Structural formulas of saccharides (80-82) and other compounds (83-89) in Cichorium glandulosum Boiss. et Huet. (Note: The sequence numbers in the figure correspond to the compound numbers in sections “Saccharides” and “Others” of the article.).
Others
The seeds of Cichorium glandulosum Boiss. et Huet are rich in volatile oil components, amino acids, as well as Ca, Mg, Zn, Fe, and Mn and other mineral elements, and its leaves are rich in vitamins and carotenoids.75,76 Various fatty acids such as palmitic acid (89), stearic acid, oleic acid and various other volatile components were also detected in chicory.6 In addition, the alkaloids 2, 3, 4, 9-tetrahydro-1H-py rido-(3, 4-β) indole-3- carboxy lic acid,5-hydroxymethyl-2-furfural (83) and azelaic acid (84) were isolated,32 and 2S, 2′S-Aurantiamide ace tate which was detected for the first time and methyl 4-hydroxyphenylacetate (85).26 It also contains other components such as britannin (86), methyl 3,4,5-trimethoxycinnamate (87), baicalin(88) 5,8,3′,4′-tetrahydroxy-7-methoxyflavone, 5,8,4′-trihydroxy-7,3′-dimethoxyflavone, etc.29 In addition to the above categories, there are other compounds in the medicinal herbs, as shown in Figure 4.
Pharmacological Activity
According to the theory of TCM, Cichorium glandulosum Boiss. et Huet has the effects of clearing the liver and promoting gallbladder, detumescence and diuresis, and strengthening the spleen and stomach. With in-depth research, it was found that the understanding of the efficacy of Cichorium glandulosum Boiss. et Huet has the same TCM and modern pharmacological research. Its modern pharmacological research focuses on the protection of the liver, regulation of blood lipids, blood glucose and uric acid (UA) metabolism, regulation of intestinal microorganisms and immune function, which correspond to the traditional uses in Chinese medicine, and its antioxidant and antitumor effects are new areas of research in recent years. The relevant pharmacological effects of Cichorium glandulosum Boiss. et Huet based on existing research are shown in Figure 5.
Biological activities and molecular mechanisms associated with Cichorium glandulosum Boiss. et Huet in the organism.
Hepatoprotective
According to the study, flavonoids, coumarins, and sesquiterpenoids in Cichorium glandulosum Boiss. et Huet have hepatoprotective effects, and the ethanol-extracted active ingredient components of its above-ground parts significantly attenuate liver pathological changes in mice with acute liver injury due to intraperitoneal administration of carbon tetrachloride or BCG vaccine.77 WeiJun Yang used carbon tetrachloride (CCl4) to induce acute hepatotoxicity in mice, and BCG vaccine (BCG) and lipopolysaccharide (LPS) were used to induce immune liver injury in mice.78 The biochemical parameters, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL), were assessed by intraperitoneal administration of Cichorium glandulosum Boiss. et Huet sesquiterpene extract to mice for 7 consecutive days, and chicory sesquiterpene extract significantly reduced the toxic effects caused by CCl4 in mice. The ensuing mechanistic study revealed that its hepatoprotective effect may involve protection against free radicals. Chicory sesquiterpene extract had a stabilizing effect on intrahepatic bile duct dysfunction in mice. Hu Liping found that Cichorium glandulosum Boiss. et Huet extract significantly inhibited the release of inflammatory factors, such as TNF-α, IFN-γ, and IL-1β, in the serum of immune liver-injured mice and attenuated immune liver injury induced by knife-legume protein A (Con A).79 Wang Xiaojie found that chicory polysaccharides played a role in the significant repair and alleviation of oxidative stress on APAP-induced drug-induced liver injury. Seed polysaccharides showed the strongest scavenging rate of DPPH radicals.80
Anti-Nonalcoholic Fatty Liver Disease
Shengjie Li induced a rat model of nonalcoholic fatty liver in SD rats by using high-fat diet.81 The rats were treated with chicory polysaccharide by gavage for 8 weeks. Liver tissue sections revealed that chicory polysaccharide could effectively alleviate liver steatosis, reduce serum total cholesterol (TC) and triglyceride (TG) levels, and reduce liver inflammation, thereby alleviating nonalcoholic fatty liver in rats. The experiment further revealed by transcriptomics and metabolomics that chicory polysaccharide could do the following: restore the expressions of Xbp1, Insig2, and other genes related to lipid metabolism in rats, inhibit adipogenesis, promote fatty acid β-oxidation, improve steatosis, and play a role in the treatment of non-alcoholic fatty liver disease (NAFLD).
Wu Yulong extracted chicory polysaccharide from chicory root and established a high-fat diet-induced non-alcoholic fatty liver model in rats.82 After 12 weeks of administration of chicory polysaccharide, the relevant indexes were detected. Chicory polysaccharide could significantly reduce blood lipids, alleviate liver damage indexes, and increase antioxidant levels in rats. The pathological section results also showed that chicory polysaccharide significantly improved the accumulation of lipid droplets and mitochondrial damage in rat hepatocytes induced by high-fat diets. Its mechanism of action may be due to the activation of the AMPK signaling pathway and the effect of chicory polysaccharide on amino acid metabolism. The mechanism of its effect is as follows. It affects the AMPK signaling pathway, upregulates the expression levels of PPARα, p-AMPKα, and p-ACC, and downregulates the levels of SREBP-1c, AMPKα, and ACC proteins to achieve the protective effect of chicory polysaccharide on rats with NAFLD induced by the high-fat diet.
Xu Fang’s microwave-assisted enzyme method was optimized, and chicory polysaccharide was extracted, the drug was administered for 35 days using the high-fat induced NAFLD model of SD rats.83 The results showed that Cichorium glandulosum Boiss. et Huet polysaccharide could reduce the weight and food intake of rats, and significantly reduce the levels of TC, TG, and low-density lipoprotein cholesterol (LDL-C) in the serum of hyperlipidemia rats, increase the content of high-density lipoprotein cholesterol (HDL-C), increase the activity of superoxide dismutase (SOD) enzyme, and significantly enhance the activity and function of antioxidant enzymes in the liver of rats. It has the function of treating hyperlipidemia and nonalcoholic fatty liver in NAFLD rats.
Maoru Li extracted and purified chicory polysaccharide and investigated its lipid-regulating effects on a zebrafish model of NAFLD.84 The experimental results showed that chicory polysaccharide could reduce hepatic steatosis in high carbohydrate diet (HCD) induced zebrafish larvae, and chicory polysaccharide could significantly reduce the model TC and TG levels, decrease the mRNA expression of srebf-1, and increase the expression of PPAR-α and β. The hypolipidemic effect of chicory polysaccharide was further found to depend mainly on the promotion of lipolysis (mainly β-oxidation) or inhibition of lipogenesis. In addition, chicory polysaccharides could prevent and cause the regression of NAFLD steatosis by inhibiting lipogenesis and promoting lipolysis through their modulating effects on lipid metabolism.
Anti-Liver Fibrosis
Cichorium glandulosum Boiss. et Huet extract (CG) has an inhibitory effect on thioacetamide-induced liver fibrosis in rats, according to the study conducted by Dongmei Qin.85,86 The CG extract inactivated serum AST and ALT in rats with liver fibrosis. HE- and Masson-stained sections of the treated group could show normal liver tissue, as well as clear liver lobules and sinusoids. Finally, immunoblotting and immunohistochemical methods revealed that the administered group could resist liver fibrosis by reducing the expression levels of FN, Smad3, and TGF-β1. In the animal model of liver fibrosis, all doses of CG volatile oil could alleviate the rat liver fibrosis model by significantly reducing the serum levels of AST, ALT, MDA, Hyp, g-GT, LDH, ALP, and Alb. Zhang Xiaoheng found that treatment with Cichorium glandulosum Boiss. et Huet extract could significantly reduce hepatocyte degeneration, necrosis, and liver fibrosis in mice, according to a liver fibrosis model. Cichorium glandulosum Boiss. et Huet extract has preventive and curative effects on liver fibrosis in mice.87
Hypoglycemic Effect
Studies show that Cichorium glandulosum Boiss. et Huet may delay the onset of diabetes and treat osteoarthritis and cardiovascular disease in clinical trials.88,89 Experiments have proved that when the insulin content is low, Cichorium glandulosum Boiss. et Huet can be preferentially used in the early stage of diabetes.
JunlinYan found that the alcoholic extract of Cichorium glandulosum Boiss. et Huet can reduce blood glucose and blood lipids, and improve insulin resistance and liver oxidative stress in db/db mice in the T2DM model.90 It was further found that chicory could affect the abundance of intestinal bacteria in db/db mice, which could lead to the regression of intestinal bacterial disorders, affect the short-chain fatty acid-producing flora, increase the production of short-chain fatty acids and thus alleviate insulin resistance.
Lotfollah Rezagholizadeh compared the anti-inflammatory effects of chicory seed aqueous extract (CSE) in rats in the early and late stages of T2DM.91 CSE significantly reduced fasting blood glucose in early diabetic rats after 21 days of administration of nicotinamide and streptozotocin in Wistar rats modeled with early diabetes and streptozotocin in the late stage. After further experiments, the mRNA and protein expression levels of IKKβ and P65 genes were elevated in both stages of T2DM, because CSE reduced their expression. CSE decreased the DNA binding ability of NF-κB in diabetic rats. This finding suggested that it can prevent and delay the onset of diabetes in the early stages of diabetes.
Manju Sharma found that Cichorium glandulosum Boiss. et Huet seed extract could exert cardioprotective effects by inhibiting oxidative stress and pro-inflammatory cytokines while helping prevent the development of diabetic complications.92 Experimental diabetic cardiomyopathy was induced by a single intraperitoneal injection of streptozotocin (STZ) combined with high energy intake in rats. Cichorium glandulosum Boiss. et Huet seed extract had significant effects on the restoration of blood glucose levels and the increase in the levels of AST, lactate dehydrogenase (LDH), SOD, thiobarbituric acid-reactive substances (TBARS), and blood glutathione (GSH).
Qin Huiyu, based on systematic pharmacological studies,93 found that Cichorium glandulosum Boiss. et Huet could treat type II diabetes with nonalcoholic fatty liver disease (T2DM-NAFLD) by regulating metabolic pathway, calcium signal pathway, PI3K/Akt, cAMP, MAPK, and other pathways. Xue Wei established a T2DM rat model and gave inulin to intervene, and found that blood glucose and blood lipids were significantly reduced in T2DM rats after inulin intervention.94 In addition, a study aims to evaluate the preventive effect of chicory extract on metabolic diseases in supplementing natural drug treatment methods. The results showed that daily oral administration of composite soaked beverages can reduce weight gain, hyperglycemia, hypertriglyceridemia, insulin resistance, and hypertension.95
Regulation of Lipid Metabolism
Lin Ding found that Cichorium glandulosum Boiss. et Huet extract (CG) was effective in reducing lipid accumulation in a rat high-fat diet model and a free fatty acid-treated hepG2 cell model.96 CG extract protected hepatocytes from damage and inflammation. Its lipid-lowering properties were found in a rat high-fat diet model and an acetaminophen-treated L02 cell model. Western blot analysis showed that these components could regulate key lipid targets, such as CD36, FATP5, and PPAR-a, at the molecular level, thereby regulating lipid oxidation and lipid uptake pathways at multiple targets. Xu Fang found that chicory polysaccharide significantly reduced serum TC, TG, and LDL-C levels and increased serum HDL-C levels in hyperlipidemic rats.83
Yilizere Aibaidula investigated the mechanism of hypolipidemic effects of lactucin and lactucopicrin from Cichorium glandulosum Boiss. et Huet on FFA-induced HepG2 cells.50 Lactucin and lactucopicrin could significantly reduce the level of TG accumulation in FFA-induced HepG2 cells and could improve their lipid degeneration. After further experiments, we learned that the mechanism may be through its effect on many key genes of lipid metabolism, such as HADHA, ADAM17, SQSTM1, and GBA, which affect the regulation of lipid metabolism. It exerts lipid-lowering effects by affecting fatty acid oxidation.
Anti-Hyperuricemia
Excessive secretion and/or decreased excretion of UA can lead to hyperuricemia. Considering the global prevalence of hyperuricemia, it has received an increasing amount of attention in the past decades. Chunsheng Zhu found that CA, chlorogenic acid, and aesculin in chicory all reduced serum UA, creatinine (Cr), and urea nitrogen (BUN) levels, which are indicators of renal function, in quail.28 Experiments further revealed that the UA-lowering efficacy of CA, chlorogenic acid, and aesculin may be due to the inhibition of xanthine oxidase and adenosine deaminase activities. Cai Meng found that chicory extract can reduce UA levels in a model of UA metabolism disorder in quail, and the mechanism of action of chicory extract against hyperuricemia was possibly the reduction of serum D-lactic acid and DAO levels, improvement of intestinal mucosal barrier, increase in intestinal villi height to crypt depth ratio (V/C), increase in intestinal tight junction Occludin protein levels, increase in probiotic population (eg, Lactobacillus), and decrease in harmful bacteria (eg, Enterococcus faecalis), which in turn affected UA metabolism.97
Yu Wang showed that chicory significantly reduced the serum UA level and increased the intestinal UA excretion in rats with 10% fructose induced hyperuricemia.98 ATP-binding cassette sub-family G member 2 (ABCG2) was expressed on the apical membrane of jejunum and ileum. Chicory significantly enhanced the expression of ABCG2 mRNA and protein in jejunum and ileum. According to a previous study,99 chicory restores intestinal microbiota by increasing probiotic flora (Bifidobacterium, Erysipelotrichaceae) and decreasing pathogenic flora (Helicobacteraceae). It promotes renal UA excretion by downregulating serum LPS and renal tissue TLR4/NF-κB inflammatory pathways, which in turn reduces the LPS/TLR4 axis inflammatory response.
Wang Yu conducted in vitro experiments and showed that chicory extract could improve UA excretion by affecting the “intestine-kidney” UA excretion pathway and that chicory extract could significantly reduce UA levels in the urine and feces of SD rats, increase AOP, and inhibit inflammation. In vitro experiments showed that chicory extract could reduce the inflammatory response caused by oxidative stress by increasing the AOP of Caco2 and HKC cells.100
Anti-Tumor
Ye Yinsong investigated the anti-proliferation effects of various active components in Cichorium glandulosum Boiss. et Huet on different tumor cells, and found that lactucin and lactucopicrin had strong inhibitory effects on breast and colon cancer cells.101 Zang Wei found that the inhibitory effects of Cichorium glandulosum Boiss. et Huet seeds and root extracts were coordinated and potentiated on HepG2 cells, and could promote apoptosis of HepG2 cells.102 Chen Jinrui found that CA could induce apoptosis in oral cancer KB cells, probably by inhibiting the expression of MMP22 and MMP29 proteins in oral cancer KB cells, as well as by inhibiting the activation of PI3K/Akt pathway and promoting the apoptosis of tumor cells.103
Gut Microbial Regulation
Haoyu Liu investigated the effect of adding Cichorium glandulosum Boiss. et Huet to the feed of pigs on their intestinal microenvironment.104 The animals maintained good performance and health regardless of the diet. Terminal restriction fragment length polymorphism technology combined with cloning and sequencing was used to assess the bacterial community structure and diversity of ileal and colonic samples. The increase in the relative abundance of colonic butyric acid-producing bacteria was positively correlated with the molar ratio of acetic acid. The increase in the relative abundance of colonic butyric acid-producing bacteria was found to be positively correlated with the molar ratio of acetic acid and correlated with the gross chicory diet. Diets containing Cichorium glandulosum Boiss. et Huet roots were correlated with the abundance of large mold colonies. Fermentation products and pH of the surimi were related to the type of diet and changes in the microbiota. This finding suggested that Cichorium glandulosum Boiss. et Huet affects the intestinal microenvironment of pigs. Wu Wei also found that chicory root ultramicro powder had a restorative effect on the disturbance of intestinal flora in cyclophosphamide-induced immunosuppressed mice.105
Immune Function Regulation
Wu Yulong found that chicory polysaccharide increased the number of erythrocytes and leukocytes in the whole blood of cyclophosphamide-induced immunosuppressed mice, and regulated the levels of IL-2, IL-6, and TNFα in immunosuppressed mice, thereby enhancing the immune function of immunosuppressed mice.106
Anti-Osteoporosis
Walaa G. Hozayen investigated the therapeutic effect of aqueous extracts of Chicory of Mao on glucocorticoid-induced osteoporosis in rats.107 The aqueous extract of Cichorium glandulosum Boiss. et Huet had a protective effect on the glucocorticoid-induced bone in rats. Chicory contains flavonoids and inulin, which can significantly reduce serum PTH, ALP, ACP, and bone tbarGSH. Moreover, antioxidant enzymes play a role.
He Ling found that CA could alleviate the symptoms of chondroarthritic cells in knee of rats and inhibit the glycosaminoglycan-like viscosity due to chondroarthritis in the knee of rats.108 CA contributed to the senescence resistance of this cell. CA reduced the loss of type II collagen, decreased FOXO4 protein and p53 protein expression, and alleviated IL-1β- and TNF-α-induced senescence and inflammation in chondroarthritic cells.
Antioxidant
Bioactive substances especially phenolics of Cichorium glandulosum Boiss. et Huet have high antioxidant activity. Lovro Sinkovič investigated the AOP of Cichorium glandulosum Boiss. et Huet plants treated with different fertilizers using in vitro DPPH radical scavenging and in vivo yeast Saccharomyces cerevisiae method. Chicory can exert antioxidant ability in vivo.109 Han Chang found that ethanolic extract of chicory stems had biological activities that could scavenge DPPH radicals and ABTS radicals.110 Wu Wei found that the GSH content and SOD enzyme activity of liver tissue of mice with liver injury were significantly increased by chicory root superfine powder.111
Yilizere Aibaidula found that the bitter pigment of lettuce in Cichorium glandulosum Boiss. et Huet significantly increased SOD activity, reduced GSH content, and reduced malondialdehyde (MDA) content in FFA-induced HepG2 cells, thus acting as an antioxidant.51 A study was conducted by feeding 30-week-old mice with an AIN-93G diet or supplementing them with 0.5% freeze-dried Brussels chicory for 20 weeks. The results showed that the administration of chicory could improve oxidative stress and promote the protection of chicory against atherosclerosis.112,113
Antibacterial
Ahmed M. Amer investigated the potential antibacterial activity of Cichorium glandulosum Boiss. et Huet; bacterial inhibition tests were carried out on a group of microorganisms using different concentrations of the extract of Chicory furfuraceae.114 The antibacterial activity was analyzed by the pore diffusion method, and the results showed a corresponding increase in the diameter of the inhibition band with increasing concentration of the solvent extract. Gram-positive bacteria were more sensitive than Gram-negative bacteria and fungi. Hazir Rahman found that chicory seed extract had strong inhibitory activity against MDR pathogenic bacteria.115 In the pore diffusion method, aqueous extracts showed higher inhibition against Pseudomonas aeruginosa (16 mm ± 0.7 mm) and Acinetobacter baumannii (13 mm ± 0.5 mm), whereas chloroform, ethanol, and hexane extracts showed higher inhibition against P. aeruginosa. Tursonnai Delishati found that the inhibition of the alcoholic extracts of Trichoderma reesei roots and stems was more significant against the tested fungi, and the macroporous resin 80% ethanol eluate showed extremely strong resistance against Escherichia coli.116 The macroporous resin 100% ethanol eluate showed extremely strong broad-spectrum resistance against all the tested fungi, especially against Aspergillus niger.
Anti-Parasitic
Miguel Peña-Espinoza found that feeding Cichorium glandulosum Boiss. et Huet reduced the number of fecal eggs and helminth burden of ruminant wrinkled stomach nematodes but did not affect intestinal helminth infections.117,118 And it was also found that the addition of chicory to the ration had a significant inhibitory effect on gastrointestinal nematodes in cattle.
Antiprotozoal Activity
Ian David Woolsey found that the extracts of Cichorium glandulosum Boiss. et Huet leaves and roots had significant protective effects on human colon adenocarcinoma (HCT-8) cells infected by Cryptosporidium parvum.119
Safety Evaluation and Toxicity
Chicory originates from the Mediterranean region and has been used as a vegetable and pasture since the 14th century. It was introduced to China in the 1970s and was used as a medicine or as food for human consumption. In the Pharmacopoeia of the People's Republic of China, the dosage of 9 to 18 g of Cichorium glandulosum Boiss. et Huet as a Chinese herbal medicine can be considered a safe dosage. Yu Wang et al studied the effect of Cichorium glandulosum Boiss. et Huet extract on 10% fructose water-induced hyperuricemia in rats, which was studied by high-dose group (10% fructose, 16.7 g·kg−1·d−1 chicory water solution), medium-dose group (10% fructose, 13.3 g·kg−1·d−1 chicory water solution) and low-dose group (10% fructose, 6.6 g·kg−1·d−1 chicory water solution) were given.100 In this range, the content range of Cichorium glandulosum Boiss. et Huet did not exhibit significant toxic effects in rats, rather in this concentration range Cichorium glandulosum Boiss. et Huet was concentration dependent for the treatment of hyperuricemic rats.120 Similarly, an experimental study of the effect of a formula containing chicory herb on male Wistar rats with hyperuricemic nephropathy, showed that the high-dose group (8.64 g·kg−1·d−1) reduced renal damage in the model group.121 Yang Qiaoli et al conducted an acute toxicity test on 20 healthy Kunming mice with the water extract of Cichorium glandulosum Boiss. et Huet. They administered the maximum dose concentration (37.5%) to the mice by gavage (0.04 mL g−1) for 14 consecutive days.118 During the test, there was no mouse death and other toxic reactions, and the anatomical results were normal.121 In addition, lactucin, a bioactive component of Cichorium glandulosum Boiss. et Huet, did not cause adverse effects at a concentration of 20 mg·kg−1·d−1 in mice.122 Based on the data from the above studies, it can be shown that Cichorium glandulosum Boiss. et Huet extract did not show toxic side effects when given at the corresponding maximum therapeutic doses in studies on rats or mice, but had some concentration-dependent therapeutic effects. Therefore, we can confirm that Cichorium glandulosum Boiss. et Huet is not toxic within the safe concentration range and can be used safely. However, in vivo and in vitro, the safe dose and side effects of small molecular compounds of Cichorium glandulosum Boiss. et Huet are not clear, and further research is needed.
Conclusion
So far, scholars at home and abroad have made a lot of progress in the study of Cichorium glandulosum Boiss. et Huet, and found that in TCM and modern pharmacological research on the efficacy of Cichorium glandulosum Boiss. et Huet has the same understanding, and modern pharmacological research on the basis of TCM continue to extend in-depth. TCM believes that Cichorium glandulosum Boiss. et Huet can clear the liver and promote gallbladder. Nowadays, Cichorium glandulosum Boiss. et Huet is used to study the protective effect on the liver, reducing UA, relieving gout and antibacterial more, and its pharmacological effects of reducing swelling and diuresis, strengthening the spleen and nourishing the stomach echo the inhibition of high blood sugar and high fatty fatty liver. Through modern pharmacological methods and means, we can elucidate the medicinal effects of Cichorium glandulosum Boiss. et Huet and further verify the mechanism of action of the traditional usage of Cichorium glandulosum Boiss. et Huet, which can provide a theoretical basis for the development of medicinal resources and the study of the medicinal properties of the Xinjiang characteristic medicinal herb Chicory.
The extraction, purification, separation, and identification of flavonoids, terpenoids, phenylpropanoids, and polysaccharides, which are the main components in Cichorium glandulosum Boiss. et Huet, have been extensively studied, but the current research on pharmacological effects is mainly at the extract level. Few studies have been reported for studying specific small molecule compounds in Cichorium glandulosum Boiss. et Huet like the above. In the study of chicory extracts, it was found that the small molecular compounds contained in Cichorium glandulosum Boiss. et Huet have complex and diverse pharmacological activities. Therefore, the study of small molecular compounds in Cichorium glandulosum Boiss. et Huet can become the focus of future research, which can expand the practical scope of chicory, a TCM, and provide new precursor compounds for new drug research and development.
Considering its high nutritional value, Cichorium glandulosum Boiss. et Huet is a high-quality vegetable and a medicinal plant that can be consumed directly. In addition to being used as a vegetable, pasture, and coffee substitute, it is also used in the research and development of health drinks and functional foods. Inulin accounts for more than 40% of the root compounds, making it a promising plant for medicinal and food applications. The plants of this genus contain rich bioactive ingredients, and with the in-depth study of the pharmacological activity of Cichorium glandulosum Boiss. et Huet, its effects (hepatoprotective effect, regulation of blood lipids and UA, antibacterial, anti-inflammatory, anti-diabetic, and immunity-boosting effects) are closely related to its chemical components, such as terpenoids, phenylpropanoids, flavonoids, phenolic acid polysaccharides, and other compounds. The current research mostly focused on the traditional therapeutic effects of chicory as an important botanical resource. The research on the mechanism and toxic side effects of specific compounds need to be intensified, the results of which would have a broad prospect for clinical studies on chicory.
Abbreviations
TCM
traditional Chinese medicine
NMR
nuclear magnetic resonance
HPLC/DAD/MS
high performance liquid chromatography-diode array detection-mass spectrometer
Jian Yang and Yi Lei: validation, formal analysis, writing—review & editing. Junlin Yan: wrote an outline of the manuscript. Yewei Zhong and Adalaiti Abudurexiti: provided photos and modified the manuscript. Huiwen Tan: revised the manuscript. Yinsong Ye: conceived the manuscript outline and reviewed the article. Rui Zhang and Fenglian Tong: revised the manuscript outline and review articles. Xiaoli Ma: project administration, conceived the outline of the manuscript, reviewed the articles, and provided photos.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the National Natural Science Foundation of China (grant number 82360721),the Natural Science Foundation of Xinjiang Uygur Autonomous Region, China (grant number 2021D01C256), and Xinjiang Uygur Autonomous Region Tianshan Talent Youth Top Talent Project, China (grant number 2022TSYCCX0104).
ORCID iD
Xiaoli Ma
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