Therapeutic Properties of Cichorium Intybus L. Roots in Liver Diseases, Diabetes and Hypercholesterolemia

Hop and Medicinal Plants, Year XXVII, No. 1-2, 2019 ISSN 2360 0179 print, ISSN 2360 0187 electronic

THERAPEUTIC PROPERTIES OF CICHORIUM INTYBUS L. ROOTS IN LIVER DISEASES, DIABETES AND HYPERCHOLESTEROLEMIA

SOCACI (IGNAT) Maria Valentina, Elena MUDURA*, Teodora Emilia COLDEA, Liana SALANȚĂ Food Engineering Department, Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Calea Florești 64, 400509, Cluj-Napoca, Cluj, Romania. *corresponding author: [email protected]

Abstract. Ancient Egyptians used Cichorium intybus L. in the management of cardiovascular diseases and as a therapeutic aid in enhancing hepatic functions. Even during the Napoleonic age, chicory was popular as a coffee substitute and England used it as the main Camp Coffee ingredient. This study focuses on highlighting the medicinal properties displayed by Cichorium intybus L. root extracts in cases of liver disorders, diabetes and hypercholesterolemia, affections which are spread all-over the globe. A few examples of functional products containing chicory root were also presented. After reviewing several in vitro and in vivo studies on chicory root extracts, it is concluded that over the last years an increasing number of researchers suggest that chicory root extracts are hepatoprotective, increase satiety, reverse insulin resistance, and enhance lipid metabolism containing cichoric acid, chlorogenic acid, and polysaccharides. Among other therapeutic properties, chicory root extracts have shown gastroprotective, anti-inflammatory, analgesic and antidiabetic attributes. There are many possible ways of using Cichorium intybus L. root extracts in order to obtain functional products with a positive impact on one’s health status. Moreover, functional foods containing chicory-root extracts are already on the market and the ease of consumption added to the increased interest for such products encourages the development of further therapeutic alternatives meant to aid in the management of liver diseases, diabetes and hypercholesterolemia. Keywords: Cichorium intybus L., chicory root, diabetes mellitus, functional products, hypercholesterolemia, liver diseases

76 Introduction

Genus Cichorium (Asteraceae family) consists of six plant species with a major geographical presence in Europe and Asia. Cichorium intybus L. or chicory is well known as a coffee substitute and is also widely used as a treatment for various conditions (Campos et al., 2017; Mohammadi et al., 2016; Street et al., 2013). Chicory is a plant used for therapeutic purposes because it exhibits hepatoprotective and gastroprotective actions, it is beneficial on a cardiovascular level, presents hypolipidemic properties, anticarcinogenic, antidiabetic anti-inflammatory, analgesic, immunological, antimicrobial, and anthelmintic actions (Saeed et al. 2017; Al-Snafi, 2016; Das, Vasudeva and Sharma, 2016; Krylova et al., 2015). Liver diseases, diabetes and hypercholesterolemia are commonly met affections which are most of the times caused by lifestyle choices. The prevalence of non-alcoholic fatty liver diseases in Europe and the Middle East is between 20-30% (Loomba and Sanyal, 2013) and on a global level is of approximately 25% (Araujo et al., 2018). On the other hand, diabetes mellitus, a group of metabolic disorders characterized by increased blood glucose concentration is predicted to rise to 10.4% in adults by 2040 (Ogurtsova et al., 2017). Obesity is well spread in adults all over the globe and is a serious public health issue which affects many children of all ages therefore it needs to be addressed via a range of approaches from early prevention of overweight and obesity to treatment of those who need it (Spinelli et al., 2019). These facts should set up a warning signal that it’s needed to look for further therapeutic alternatives. The pharmaceutical agents recommended in the management of these affections are aiming antioxidant, anti-inflammatory, hepatoprotective, hypolipidemic, and anti-hyperglycemic actions and chicory root extracts are thought to provide similar therapeutic benefits.

Materials and methods

This study aimed at collecting and reviewing data from diverse investigations and ethnopharmacological reports in order to highlight the beneficial proprieties of chicory root extracts in liver diseases, diabetes, hyperlipidemia and hypercholesterolemia. We used web databases such as Google Scholar, PubMed, ScienceDirect, Scifinder, Scopus, and Web of Science. The searches were conducted using “chicory root” as the main

77 keywords together with “AND” operator followed by “liver diseases”, “diabetes”, “hypercholesterolemia”, ”functional products” . The review covers publications written in English, conducted over the last 5 to 10 years. The main research questions are: “Do common Romanian uncultivated medicinal plants such as Cichorium intybus L. present therapeutic properties in liver diseases, diabetes, and hypercholesterolemia?” and “What functional products are there already obtained using chicory root extracts?”. To valorize commonly found medicinal plants such as Cichorium intybus L. it is required to evaluate their potential as rich sources of bioactive components useful for obtaining functional products meant to alleviate hepatic diseases, diabetes, and hypercholesterolemia.

Results and discussions

Cichorium intybus L. is cherished for its anti-hepatotoxic properties therefore chicory extracts are found in supplements such as Liv 52 (Himalaya Drugs Co, Bombay) and Syliv (Systemic Pharmaceuticals, Allahabad). Also, in what regards patented products obtained using chicory among other plants and vegetables, there is a drink prepared mainly from chicory root extract and fermented Kefir-like methodology, there is as well as chicory extract with cosmetic application obtained from the aerial parts of the chicory which is supposed to prevent ageing, and a hydrosoluble product obtained from chicory and inulin as a coffee substitute (Bais and Ravishankar, 2001). As for the cichoric acid contained by chicory, it is shown that it has the ability of reversing insulin resistance and to suppress the inflammatory responses induced by glucosamine in HepG2 cells (Zhu et al., 2015). Moreover, polysaccharides extracted from Cichorium intybus L. demonstrated a significant attenuation of non-alcoholic steatohepatitis induced in rats through high-fat diet. It seems like chicory polysaccharides are efficacious in the management of non-alcoholic steatohepatitis by activating protein kinase (Wu et al., 2018). Next, we can speculate that the hydrosoluble chicory extract is a potential candidate in the therapy of various hepatic diseases. For example, current studies indicate that chicory extract exhibits a powerful hepatoprotective action in hepatic lesions induced by dexamethasone (Soliman et al., 2016). Roasted chicory root administered to mice acts as a prebiotic and appetite regulator increasing satiety hormones like CCK and GLP-1 (Foure et al., 2018). If caused by excessive nutrition, non-alcoholic steatohepatitis can

78 perhaps be prevented by administering chicory root given that it regulates satiety hormones. Chicory extracts can be taken into account as having natural substances beneficial in improving oxidative stress and in alleviating hepatic lesions (Saggu et al., 2014). It is well known that hepatic lesions are not resulted only from excessive nutrition but also by exposure to certain toxic substances. A study conducted in 2010 investigated the effect of adding powdered chicory in the diet of murine models suffering from hepatic injury and oxidative stress induced by nitrosamine precursors. It was noted that the mice group with hepatic lesions induced by chlorpromazine, a substance administered in the treatment of psychotic disorders, and which weren’t fed the chicory powder showed the growth of oxidative stress markers TBARS, increased total lipid content, total cholesterol, bilirubin and enzymatic activity in serum and hepatic tissue. On the other hand, the mice group that also had the chicory powder added to their diet presented a modulation in the values mentioned previously, with reduces TBARS and obvious improvement of the investigated biochemical and antioxidant parameters (Hassan and Yousef, 2010). In the view of these results, the authors concluded that chicory has a promising role in relieving oxidative stress and liver damage caused by nitrosamine compounds. As for the other compounds found in chicory we can look into the findings of Sánchez-Mata et al. (2012) who concluded that among other bioactive compounds their chicory extract contained 60% malic acid (between 1.7mg-202.12mg/100g). It was also noted that Spanish chicory, collected from 2 harvesting locations measured a pH between 4.62 and 6.21 th. Titratable acidity was measured between 0.30 and 1.67 ±30 (meq NaOH/100g) while dry matter was between 11.96 and 12.61 g/100g. Apparently, the phytochemicals and plant constituents are distributed throughout the whole plant but they are most abundant in the root (Bais and Ravishankar, 2001). Inulin extracted from chicory is a compound with therapeutic properties, it is considered to work as a prebiotic and according to several studies its usage as an ingredient in functional drinks is suitable for managing lipid metabolism and to regulate insulin and glucose levels (Ahmed and Rashid, 2017; Weitkunat et al., 2015). Purine-rich diets can contribute to the development of hyperuricemia, hypertriglyceridemia and central obesity, this process contributing to metabolic conditions resulting in renal and liver disease. In Table 1. there is the summarized list of Cichorium intybus L. extracts, their applications in liver diseases, diabetes and hypercholesterolemia. 79

Table 1. Chicory root extracts and their activity in different disorders Extract Therapeutic action In vivo/In vitro References In vivo, murine Chicory extract models with Ferrare, K. et (cichoric acid, Hypoglycemic effect streptozotocin- al., 2018 chlorogenic acid) induced diabetes In vivo, murine Chicory root Alleviates fatty liver models, fatty Wu, Y. et al., extract disease by activating liver disease 2018 (polysaccharides) protein kinase - induced by hyperlipidic diet Chicory root In vivo, murine Increases CCK and powder (inulin, models fed with Foure, M. et GLP-1 hormone levels, sesquiterpene different al., 2018 increases satiety lactones) chicory powder Anti-inflammatory Inulin chicory Lepczynski, A. action, oxidative stress In vivo, pigs extract et al., 2017 regulator Reverses insulin In vitro, resistance, suppresses glucosamine- Zhu, D. et al., Chicoric acid inflammatory treated human 2015 responses HepG2 cell In vivo, murine Alleviates oxidative models with Chicory leaf Saggu, S. et stress and hepatic hepatic lesions extract al., 2014 lesions induced by 4- tert-octylphenol Lowers uric acid and In vivo, triglyceride levels and Lin, Z. et al., Inulin extract hyperuricemia reduces abdominal fat 2014 in quails accumulation In vivo, murine Alleviates oxidative models, hepatic Hassan, H. A Powdered stress and modulates lesions- sodium and Yousef, chicory root hepatic lipidic nitrates and M.I., 2010 metabolism chlorpromazine

In a model of hyperuricemia, inulin extracted from chicory had an impact in lowering uric acid, triglycerides and abdominal fat deposits. These it is presumed to be achieved by the inulin’s ability to regulate acetyl-CoA

80 carboxylase protein through modulating the fatty acids synthesis and xanthine oxidase (Lin et al., 2014). Powdered inulin extracted from chicory was studied on pigs and it has shown that it caused significant changes in the expression of hepatic cytoskeletal proteins and in the modulation of oxidative stress and anti- inflammatory activity (Lepczynski et al., 2017). Some of the negative effects of high cholesterol diets on murine models were proven to be diminished by administering hydrosoluble chicory root extract (Kim and Shin, 1998). The results showed that by administering chicory extracts in a hyperlipidic diet resulted in higher serum HDL content than LDL, decreased lipid and triglyceride levels in hepatic tissue. It was also noted that there was a higher concentration of cecal propionic acid and an accelerated lipid, cholesterol and bile acid excretion. The authors resumed that such beneficial actions can be attributed to the changes caused to cholesterol absorption and synthesis through changed cecal fermentation and increased excretion of lipids, cholesterol and bile acid. Along with the hypolipidemic effect of chicory there is as well the hypoglycemic action attributed to it. For example, in streptozotocin-induced diabetes a natural chicory extract (chlorogenic and chicory acid) had hypoglycemic action (Ferrare et al., 2018). In other cases, chicoric acid demonstrated antihyperglycemic properties due to its peripheric influence on the glucose absorption at muscular level (Azay-Milhau et al., 2013).

Functional drinks containing chicory

Products made with a nutritional and functional role in the human body are an effective and safe alternative in maintaining homeostasis and in preventing the occurrence and the evolution of diseases. The consumption of functional drinks should be easily integrated into the individual’s daily activity this representing an accessible opportunity for improving one’s overall health status. Chicory has a rich history, ancient Egyptians used it for treating cardiovascular diseases and to enhance liver function. We can find chicory recorded even in their Papyrus Ebers. During the Napoleonic age, chicory was popular as a coffee substitute and in England, during the 2nd World War, chicory essence was used in the industry as the main ingredient of the renowned Camp Coffee (Howard, 1987). Traditional medicine uses Cichorium intybus L. roots and leaves in the preparing herbal remedies with beneficial properties in digestive stimulation and nutrient metabolism. Chicory root especially is a rich source of polyphenols proven to improve overall health status. Due to its therapeutic 81 properties, we can find chicory root used at different concentrations in the preparation of bioactive yogurts. A study conducted on this subject had shown that a bioactive yogurt containing 1% chicory root extract had the best score in sensory evaluation and pointed out that further studies are needed for establishing the synergistic relationship of chicory root extracts and probiotics (Jeong et al., 2017). Another example is a functional drink obtained mainly from burdock root with added ginger juice and 10% chicory root. The study concluded that a beverage obtained by adding chicory root extracts is a generous source of bioactive compounds and soluble fibers. Such a functional drink has a unique organoleptic profile and diabetic patients can consume it as an aid to their therapy (Chesnokova, 2015). Chicory root can be used as it is, or it can subject to extraction procedures in order to use furthermore only certain compounds. While designing a functional yogurt, it was shown that inulin and oligofructose found in chicory can be used to substitute glycemic carbohydrates in the production of functional foods and drinks. Functional yogurts with substituted compounds reduced postprandial glycemia depending of the degree of glycemic carbohydrate replacement with chicory extract (Lightowler et al., 2018). Koumiss is 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. Higher scores for flavour, aroma and texture were recorded by the study in the cases where the Koumis formula contained 1% chicory root extract in comparison with 2-3% chicory concentrations (Kim et al., 2017).

Conclusions

Chicory root is most commonly used as a coffee substitute, however, there are several chicory extracts which have shown that inulin from chicory root enhances lipid metabolism and can alleviate fatty liver diseases induced by hyperlipidic diet in murine models. Chicoric acid extracted from chicory root was shown to reverse insulin resistance and suppresses inflammatory responses in vitro, on glucosamine treated human HepG2 cells. Chicory extracts seem to alleviate oxidative stress and to modulate hepatic lipidic metabolism. It would be required to study more in depth if chicory root extracts are able to help in the management of non-alcoholic steatohepatitis and non-alcoholic fatty liver diseases. However, due to its

82 therapeutic actions on diabetes and hepatic lesions reported so far, chicory root can be considered as a potential candidate in the management of liver diseases, diabetes, and hypercholesterolemia. In traditional medicine, chicory root was used for preparing herbal remedies with beneficial properties in digestive stimulation and nutrient metabolism. Today, chicory root extracts are added to bioactive yogurts; inulin and oligofructose obtained from chicory root are incorporated in functional yogurts to aid in the management of diabetes; and there are some traditional drinks such as Koumiss reinvented to address cardiovascular diseases and to maintain a healthy digestive system. Cichorium intybus L. should be an important subject for future research in pharmacotherapy, biotechnology, horticulture and food sciences especially given its therapeutic properties in liver diseases, diabetes, and hypercholesterolemia. Moreover, this medicinal plant of the spontaneous flora can be used for developing functional foods through accessible sources of ingredients and by promoting a beneficial impact on one’s health status.

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