Jie LIANG, Xiaosi CHEN, Dongfang HUANG, Jinyu WEI, Huihua CHEN, Jinli QI, Jue HU, Lichun ZHAO*

1.Guangxi University of Chinese Medicine, Nanning 530200, China; 2.Guangxi Zhuang Yao Medicine Center of Engineering and Technology, Nanning 530200, China; 3.Guangxi Superior Chinese Patent Medicine and National Medicine Development Engineering Technology Center, Nanning 530200, China

Abstract With the rapid social development, people’s living habits have undergone great changes. Fast-paced lifestyles have led to an increase in people’s unhealthy living habits, especially in diet, such as unreasonable dietary structure and irregular diet. In this situation, the number of patients with hyperuricemia has also been increasing, and the hyperuricemia trend is becoming younger. Clinically, western medicines for lowering uric acid are commonly used, which are not safe and have the risk of injuring the liver and kidney functions. Cichorium intybus L. as a medicinal and edible material, plays an important role in treating the hyperuricemia. Recent studies have shown that C. intybus has significant effect of lowering the uric acid. This paper reviewed the experimental studies of C. intybus inhibiting uric acid production and promoting uric acid excretion, discussed its therapeutic effects and action mechanism, to provide a reference for the development of C. intybus drugs for lowering the uric acid.

Key words Cichorium intybus L., Hyperuricemia, Lowering the uric acid

1 Introduction

Hyperuricemia (HUA) is a metabolic disease characterized by abnormal uric acid. With the gradual improvement of people’s material living standards, the incidence of hyperuricemia is increasing[1-3]. Due to the imbalance of uric acid metabolism in the patients, the uric acid in the body is difficult to be discharged in time, forming uric acid deposits, leading to a series of complications, such as gout[4], making the patient painful and seriously affecting their quality of life. Uric acid deposits in the joints will cause gout. Gout is currently a main disease that affects people’s health and daily life. Gout patients not only have to suffer long-term pain, but also take regular medication, which is a heavy financial burden. What is worse, it is extremely difficult to cure this disease.

At present, the clinical prevention and treatment of hyperuricemia are mainly from the three aspects of reducing uric acid production, promoting uric acid excretion and promoting uric acid oxidation. Therefore, the effect of drugs is also achieved mainly through these three ways. Drugs commonly used clinically to inhibit uric acid synthesis include xanthine oxidase inhibitors such as allopurinol and febuxostat; drugs used clinically to promote uric acid excretion are URAT1 inhibitors such as sulfinpyrazone[5]. There is another drug whose main function is to promote the oxidation of uric acid. At present, there are few such drugs available in the clinic, only rasburicase, while other drugs have not been put into clinical practice temporarily and are still in the development stage. Western medicines have certain effects in the prevention and treatment of hyperuricemia, but their side effects are relatively significant. Taking too much western medicines may cause damage to the patient’s health. There are certain contraindications in use. Some drugs cannot be taken for a long time, and some drugs are forbidden for patients with renal insufficiency and kidney stones. Once taken by mistake, it will cause serious consequences. Therefore, it is urgently necessary to find effective and long-term use of drugs for the medical community and the majority of patients with hyperuricemia.

CichoriumintybusL. is a common Chinese medicine. Its medicinal part is its root or dry ground part. It has good medicinal value and can be eaten directly. Its roots are rich in inulin and aromatic substances. Specific substances can be extracted by chemical extraction methods and used in the production of substitute coffee, which can enhance the digestive function of the human body.C.intybuscan be eaten for a long time without harm to the human body. It can even become a kind of food on people’s table, allowing people to achieve the purpose of preventing and curing diseases through correct and reasonable daily eating. As a kind of edible and medicinal material,C.intybusavoids the side effects of improper medication or wrong compatibility to a certain extent. Both the root and ground part ofC.intybuscan be used as medicine. It is slightly bitter and salty in taste. It is generally used for diuresis and swelling, clearing away heat and detoxification. It also has a certain effect on stomach invigoration. Modern pharmacological research has shown that it has obvious curative effect on hyperuricemia[6]. Through many experiments, Chinese scholars have proved thatC.intybusextract can exhibit a significant uric acid-lowering effect on the animal model of hyperuricemia, which is mainly reflected in promoting uric acid excretion and inhibiting uric acid production.

2 Mechanism of inhibiting the production of uric acid of C. intybus

Uric acid (UA) comes from purines in the body. Food is decomposed into a large number of purines after being absorbed by the body. Through the decomposition and conversion of purines and feedback regulation in the decomposition process, and the final product is uric acid. The main enzymes that produce uric acid are as follows: 5′-nucleotidase (5′-NT), adenosine deaminase (ADA), guanine deaminase (GDA), xanthine oxidase (XOD), and purine nucleoside phosphorylase (PNP). These five types of enzymes play an important role in the conversion process. The production of uric acid is affected by enzyme activity, which is mainly manifested by the difference in production speed. If enzyme activity is abnormal, the production of uric acid will inevitably be affected[7].

Through studying theinvitroxanthine oxidase inhibitory activity ofC.intybus, Liu Luetal.[8]found that the alcohol extract ofC.intybusstems and leaves had a great inhibitory effect on xanthine oxidase. In the control experiment, the enzyme activity of the experimental group was significantly affected, and the inhibitory effect reached 61.2%. Zhang Bing, Liu Xiaoqingetal.[9-10]fed uric acid and uricase inhibitor diets to Kunming mice and C57 mice, and found thatC.intybusextract has a better anti-hyperuric acid effect in the experiment. Through in-depth research, it was also found that in animal hyperuricemia models,C.intybusextract has a significant effect on alleviating symptoms. Through feedingC.intybusextract, the uric acid level of animal model of quail hyperuricemia can be rapidly decreased and returned to normal levels, and lasted for a long time, the original hyperuricemia was well controlled, and the symptoms were significantly improved. Through experimental research, Lin Zhijianetal.[12]pointed out thatC.intybusextract also has a significant effect on the reduction of serum XOD activity, which in turn affects the metabolism of uric acid and can also regulate the production of uric acid; the study also found thatC.intybusextract can inhibit the activity of serum reduced coenzyme II (NADPH), which may inhibit the production of uric acid by interfering with pentose phosphate pathway; the study also showed that the regulatory effect ofC.intybusextract on hyperuricemia may be achieved by interfering with XOD metabolism. Huang Shengnanetal.[13]established a HUA model, fed a high-purine diet and usedC.intybusas an intervention substance, and obtained the results:C.intybusy had a strong inhibitory effect on the decomposition of purines, it could inhibit the activity of metabolic enzymes (5′-NT, GDA, PNP, ADA), such as inhibiting 5′-NT activity and slowing down the conversion of purine nucleosides; the decrease of ADA activity can lead to the decrease of Xanthosine; the decrease of PNP reaction can cause the purine conversion process to be inhibited; the decrease of XOD activity can directly reduce the production of uric acid.

3 Mechanism of promoting the discharge of uric acid of C. intybus

Hyperuricemia is divided into two types: primary and secondary. The main pathogenesis is insufficient uric acid excretion, which leads to increased uric acid levels in patients. This is related to the strong production of uric acid or the slowing down of excretion. The kidney is the most important organ for the excretion of uric acid, which accounts for about 66% of the excretion. Another excretion route is intestinal excretion. From the references, it can be known that most patients with hyperuricemia have problems with renal reabsorption, and the proportion of patients with renal reabsorption dysfunction is about 90%[14]. The excretion of uric acid through the kidneys requires the use of transporters. The more important ones are Glut9 (glucose transporter family member 9), OAT1 (organic anion transporter 1), OAT3 (organic anion transporter 3),etc. If the transporter is absent, the absorption or excretion of uric acid can be disturbed, thereby affecting the level of uric acid.

There are three forms of renal excretion of uric acid (glomerular filtration, reabsorption of renal tubules and collecting ducts, and re-secretion after reabsorption). According to statistics, nearly 98% of uric acid after glomerular filtration is reabsorbed through the renal tubules[15]. Glut9 detection indicators can be used as the diagnostic criteria for hyperuricemia. Through feeding 10% fructose drinking water, Wang Yuetal.[16]established a hyperuricemia SD rat model, analyzed the effect of traditional Chinese medicineC.intybusextract in the regulation of uric acid, and assessed whether it affects the expression of Glut9 in the kidney, and found that in the expression of Glut9 in the kidney,C.intybusextract has a good inhibitory effect, and can accelerate the excretion of uric acid and reduce the reabsorption effect.

The organic anion transporter (like OAT3) is located in the basal side membrane of the proximal convoluted tubule of the kidney, and plays an important role in the transport of organic anions. Through the combination of transporters, it assists organic anions to enter the blood and urine, and also participates in the secretion of urate in the kidneys. As the production of uric acid increases, the body’s uric acid metabolism is unbalanced, indicating that the transporter is closely related to the formation of hyperuricemia[17-18]. Through experiment, KOEPSELLHetal.[19-20]found that the expression level of OAT3 in the kidney is closely related to the level of uric acid. If the expression level decreases, the blood uric acid level will rise. Li Liyuetal.[21]built a quail HUA model, and named one of the gene sequences with 50% similarity to human hOAT3 as OAT3-LIKE. In the experiment, they found thatC.intybusreduces the level of blood uric acid in quail, the expression of OAT3-LIKE gene is significantly enhanced, and the secretion of urate increases.

4 Mechanism of preventing and treating the hyperlipidemia of C. intybus

At present, the uric acid-lowering drugs are mainly divided into two categories according to their efficacy. One category plays a role in the process of uric acid production, reducing uric acid by strengthening the inhibition of key enzyme activities in the production process, including allopurinol, and the other category exerts an effect in the process of excretion, increasing the excretion of uric acid and strengthening the excretion effect of the kidneys, such as benzbromarone[22]. However, these drugs also have certain disadvantages during their use. Research has found that although these drugs have obvious effects, long-term use often causes severe damage to the patient’s body, such as gastrointestinal and liver damage[23-25]. Zhu Chunshengetal.[26]established a quail hyperuricemia model, carried out a control experiment to explore the efficacy ofC.intybusextract, and divided into 5 groups: control group, model group, benzbromarone group (20 mg/kg), mixture high-dose group (cichoric acid, chlorogenic acid, and esculin doses were 150 mg/kg), mixture low-dose group (cichoric acid, chlorogenic acid, and esculin doses were 50 mg/kg). After 3 weeks of administration, they collected serum uric acid levels, liver function indicators including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and renal function indicators (creatinine and urea nitrogen levels), and made a record of the changes in the activities of adenosine deaminase and xanthine oxidase, which are related to UA metabolism. They obtained the following conclusions: the mixture had a significant effect in lowering uric acid; the uric acid level of the group usingC.intybusextract was maintained for a longer time and the level remained stable; compared with the western medicine group as a comparison, it had obvious advantages, including better curative effect and no liver damage,etc., while the western medicine group had liver damage in the quail after the drug reached a certain amount. After analysis, it was found that chlorogenic acid, esculin , and cichoric acid inC.intybusextract may be the main substances and play an effective role in controlling the level of uric acid, and it is safer and more stable than commonly used drugs, and the reason for the inhibition may be the inhibition of XOD and ADA activity, and the enzyme activity is affected by the related substances in the extract and is denatured or inhibited.

At present, many uric acid-lowering drugs commonly used in clinical practice may cause liver damage. Commonly used western medicines for uric acid-lowering all have such side effects, and there are great disadvantages in their use[27-28]. In view of this, in the treatment of hyperuricemia, we can also consider the intestinal excretion. In the excretion of uric acid, the intestine is one of the ways, so the intestine can also be used as an important target organ to develop new drugs[29]. Using the fructose drinking water with a mass concentration of 100 g/L, Wang Yuetal.[30]prepare a hyperuricemia rat model to detect serum uric acid (SUA), excretion of fecal uric acid (FUA), and serum diamine oxidase (DAO) levels. Then, they used Elisa method to detect serum D-lactic acid, serum endotoxin lipopdysaccharide (LPS), intestinal secretory immunoglobulin A (sIgA), intestinal β-defensin 1 (DEFB1) levels, used HE staining method to observe intestinal pathology, used Eric-PCR fingerprinting to analyze the macroscopic structure of intestinal flora, and used the real-time fluorescent PCR to analyze the intestinal tract. The results show thatC.intybusextract can significantly reduce the levels of SUA, FUA, DAO, D-lactic acid, LPS and DEFB1 in the intestines of model rats, increase the level of intestinal sIgA, and improve the morphology of intestinal tissues and the macroscopic structure of intestinal flora in model animals. Among them, the number ofEscherichiacoliandEnterococcusfaecaliswas greatly reduced, and the proportion of bifidobacteria was increased; the intestinal flora environment of the experimental group was significantly improved; thus, they reached the conclusion that the abnormal excretion of intestinal uric acid lies in the pathological change of the intestinal barrier. The influence of many factors leads to abnormal changes in the intestinal environment. Therefore, the treatment can start from the intestinal environment to improve the intestinal barrier, maintain the intestinal homeostasis, and maintain the normal intestinal environment, which is also an important guarantee for the effectiveness ofC.intybusextract.

In addition, since hyperuricemia is a metabolic disease, adjusting and improving metabolic disorders in the body has become a new starting point for its prevention and treatment, which is also a hot spot in current research. Niu Hongjuan[31]proposed that sweeteners have a greater impact on the environment of the intestinal flora. Through experiment, it has found that the proportion of pathogenic bacteriaE.coliand Lactobacillus have increased in rat research, and the number of bacteria has increased greatly. In hyperuricemia, the inhibition of enzyme activity can be achieved through taking nutritive sweeteners, so that the production rate of uric acid can be slowed down and effectively controlled, and the environment of the intestinal flora can be improved.C.intybuspolysaccharides can significantly improve the intestinal flora and reduce the reproduction of harmful bacteria in the intestines. Experiments have found that pathogenic bacteria are significantly inhibited, while the number of probiotics Bifidobacterium and Lactobacillus in the intestine has increased, and the proportion of beneficial bacteria in the whole group has been greatly increased, accordingly providing a good metabolic environment for stable intestinal excretion.

5 Discussion

Hyperuricemia often occurs in middle-aged and elderly men and postmenopausal women[32]. At present, the average age of incidence of hyperuricemia in China is gradually dropping, but the proportion in the population is gradually increasing. Hyperuricemia and its complications such as gout are generally caused by impaired metabolism of purine or uric acid. The final metabolite of human purine is uric acid, so the main idea of treating hyperuricemia is to inhibit the production of uric acid and enhance excretion. This is consistent with the efficacy ofC.intybus, such as diuresis and swelling, clearing dampness-heat of gallbladder and liver, so as to significantly reduce uric acid, andC.intybushas a multi-channel multi-target effect. Studies have shown thatC.intybuscan reduce uric acid by reducing urate metabolism enzymes and key reaction enzymes, such as reducing the activity of xanthine oxidase. Therefore, it is feasible to start from the kidney and intestinal excretion, inhibit reabsorption and regulate the intestinal environment, to realize the balance of uric acid metabolism. The main uric acid-lowering drugs inC.intybusmay be esculin, chlorogenic acid, and cichoric acid. These substances are non-toxic and will not cause serious liver and kidney damage. However, the effective ingredients and treatment mechanisms ofC.intybusto prevent hyperuricemia are not clear yet, which limits the development ofC.intybus-based uric acid-lowering drugs. In the future, it is necessary to strengthen multidisciplinary research to clarify the action mechanism ofC.intybusin the treatment of hyperuricemia and provide clinical assistance.