Research Progress of Herb Pair Rhizoma Coptidis-Fructus Evodiae

Lingyu DENG, Huizhen QIN, Si LIN, Jing LUO, Anda WEI, Fengfeng XIE, Hua ZHU

Abstract The herb pair is the basic form of compatibility and application of traditional Chinese medicine. Herb pairs have the advantages of simple structure， clear compatibility and effective characteristics， and are suitable for scientific research. Rhizoma Coptidis-Fructus Evodiae is a relatively fixed combination of two herbs commonly used in clinical Chinese medicine. Chinese medicine uses it to treat various diseases caused by damp-heat accumulation in the liver and gallbladder， and spleen and stomach. The two medicines in the herb pair are opposite in nature but complement each other， and can achieve a great effect based on simple combination. Modern research shows that the herb pair has a wide range of pharmacological effects and good anti-tumor， analgesic， bacteriostatic and anti-inflammatory activity， and show good curative effects on stress ulcers， functional dyspepsia， chronic colitis， etc. This paper reviewed the research progress on the herb pair of Rhizoma Coptidis-Fructus Evodiae.

Key words Rhizoma Coptidis-Fructus Evodiae; Medicine pair; Research progress

Received： April 5， 2022  Accepted： June 5， 2022

Supported by Collaborative Innovation Center of Zhuang and Yao Ethnic Medicine （GJKY [2013]20）; Guangxi Key Laboratory of Zhuang and Yao Ethnic Medicine （GKJZ [2014]32）; Guangxi Ethnic Medicine Resources and Application Research Center of Engineering （GFGGJH [2020]2605）; Guangxi Key Discipline： Zhuang Ethnic Medicine （GZXK-Z-20-64）; The Eighth Batch of Special Expert Projects of Guangxi Zhuang Autonomous Region （GRCTZ [2019] 13）; Guangxi Key Research and Development Project （GK AB21196016）; National Natural Science Foundation of China （82060695）; Guangxi Science and Technology Base and Talent Project （GK AD21238031）; Guangxi Zhuang Autonomous Region Philosophy and Social Science Planning Research Project （20BMZ005）; Foreign Expert Project of the Ministry of Science and Technology of the Peoples Republic of China （GXL20200233001）; Guangxi First-class Discipline of Traditional Chinese Medicine： Ethnic Medicine （GJKY [2018]12）.

Lingyu DENG （1997-）， female， P. R. China， master， devoted to research about traditional Chinese medicine identification and quality standards.

*Corresponding author. E-mail： zhuhuagx@163.com; 15177143553@163.com.

Coptis chinensis Franch. is a common plant of Ranunculaceae. Its main medicinal parts are rhizomes， and Rhizoma Coptidis tastes bitter and is cold in nature. It is attributive to the heart， spleen， stomach， liver， and gallbladder meridians. Because of its bitter and cold nature， Rhizoma Coptidis has the effects of clearing away heat and dampness， and purging fire for removing toxin. It is often used to treat toothache， sore mouth and tongue， and gingival hemorrhage caused by heart fire and upper inflammation， and can also be used for abdominal fullness， hiccups and acid reflux caused by damp and heat stagnating. Euodia rutaecarpa （Juss.） Benth. is a herb of Rutaceae， often used as a therapeutic drug with its dried and nearly mature fruits. Fructus Evodiae smells fragrant and spicy， and is bitter in taste. It is a commonly used interior-warming medicine， attributed to the liver， spleen， kidney and stomach meridians. Because of its warm and pungent properties， it has the functions of expelling cold and relieving pain， and harmonizing the stomach， and is often used to treat pain， vomiting， hiccups， diarrhea， etc.[1]. The formula for the compatibility of the herb pair Rhizoma Coptidis and Fructus Evodiae was originally recorded in Zhuyu Pills in Taiping Shenghui Fang in the Song Dynasty. It is commonly used in traditional Chinese medicine to treat various diseases caused by damp-heat accumulation in the liver， gallbladder， spleen and stomach， and large intestine， and had been proven for its clinical efficacy by experienced physicians of past generations.

Historical Evolution of the Processing of Rhizoma Coptidis-Fructus Evodiae

The processing of medicines in China has a history of more than 2 000 years. From the earliest Spring and Autumn Period and the Warring States Period to the present 21st century， the processing techniques of medicines have been gradually improved. Rhizoma Coptidis prepared with Fructus Evodiae juice first appeared in Hanshi Yitong in the Ming Dynasty. It is a typical "using corrigent" method in which that the pungent and hot nature of Fructus Evodiae inhibits the bitter and cold nature of Rhizoma Coptidis. Rhizoma Coptidis-Fructus Evodiae is made from the juice of Rhizoma Coptidis and Fructus Evodiae， in which Rhizoma Coptidis is bitter and cold and Fructus Evodiae is pungent and hot. The two， of which one is cold and the other is hot， and one is yin and the other is yang， suppress and reconcile each other， and achieve detoxification and synergy， so that the properties of the drugs are changed， making them more safe and reasonable to meet clinical drug use[2].

Chemical Constituents of Rhizoma Coptidis-Fructus Evodiae

Alkaloids

Because of its bitter and cold nature， Rhizoma Coptidis is rich in a large amount of alkaloids， such as berberine， coptisine， palmatine， epiberberine， etc. Fructus Evodiae is a pungent and hot medicine. The processing and use of the two can reduce the bitterness and coldness of Rhizoma Coptidis and decrease the content of related alkaloids. Studies have found that the main chemical components of Rhizoma Coptidis are alkaloids， and a few are acids or lactones. Zhang et al.[3] found through experiments that there were great differences in chemical composition between Rhizoma Coptidis and Rhizoma Coptidis-Fructus Evodiae. Berbamine and other components in Huanglian Tablets were not detected in Rhizoma Coptidis-Fructus Evodiae， while related components of Fructus Evodiae were added in the detection of Rhizoma Coptidis-Fructus Evodiae. The difference in composition between Rhizoma Coptidis-Fructus Evodiae and Huanglian Tablets may be the reason for the decrease in the bitterness and coldness of Rhizoma Coptidis-Fructus Evodiae.

Peng et al.[4] found by analyzing under optimized RP-HPLC conditions and comparing the chromatograms that the dissolution rate of alkaloids in Rhizoma Coptidis could be reduced when Rhizoma Coptidis and Fructus Evodiae were used together， while the compatible use in Zuojin Pill （Rhizoma Coptidis∶Fructus Evodiae=6∶1） was beneficial to the dissolution of evodiamine.

Deng[5] in the study to verify how the dissolution of Rhizoma Coptidis and Fructus Evodiae will be affected when they are mixed in different proportions， through the method of combining in-vitro dissolution （chemical composition） and in-vivo absorption， found that the dissolution of Rhizoma Coptidis and Fructus Evodiae increased with the increase of the proportion of the other one， while berberine in Rhizoma Coptidis was the opposite， and its dissolution decreased with the increase of the proportion of Fructus Evodiae.

Volatile oil

Fructus Evodiae has a strong aroma and a spicy and bitter taste. The chemical constituents of Fructus Evodiae are mainly alkaloids： evodiamine and rutaecarpin. Besides， Fructus Evodiae also contains volatile oil components. Lu et al.[6] investigated the effect of the compatible use of Rhizoma Coptidis and Fructus Evodiae on the volatile oil components through research. They found that after the compatible use of Rhizoma Coptidis and Fructus Evodiae， the content of most small-molecule volatile oils decreased， and some individuals showed a larger increase. The reason for this phenomenon may be that the solubility of drugs increases during the decoction process， or some chemical reactions occur.

Pharmacological Study of Rhizoma Coptidis-Fructus Evodiae

The enduring secret for the compatible use of Rhizoma Coptidis and Fructus Evodia， from ancient times to the present， is due to its excellent pharmacological effects. Studies have confirmed that under the guidance of the theory of traditional Chinese medicine， the proportion of Rhizoma Coptidis and Fructus Evodiae can be adjusted， or a certain bias property of Rhizoma Coptidis and Fructus Evodiae can be changed or inhibited， so as to reduce toxic side effects and expand the scope of medication. The compatibility of Rhizoma Coptidis and Fructus Evodiae is commonly used in the treatment of cancer， tumor， inflammation， gastrointestinal diseases， hyperlipidemia， cardiovascular diseases and other diseases[7].

Antitumor effect

Modern research has shown that Rhizoma Coptidis has the effect of inhibiting the proliferation of tumor cells after being processed with Fructus Evodiae Juice. Recent studies have found that berberine and evodiamine， the main active components of Rhizoma Coptidis-Fructus Evodiae， have anti-tumor activity， indicating that Rhizoma Coptidis and Fructus Evodiae both have the effect of inhibiting the proliferation of tumor cells， and berberine has strong activity on HepG2 cells[8].

Anti-cancer effect

The related compatibility of Rhizoma Coptidis and Fructus Evodiae is often used to treat gastrointestinal diseases. Studies have shown that Rhizoma Coptidis and Fructus Evodiae can inhibit the activity of gastric cancer cells. Zheng et al.[9] showed by using the network pharmacology technology that the therapeutic effect of Rhizoma Coptidis-Fructus Evodiae on gastric cancer embodies the multi-component-multi-target characteristics of traditional Chinese medicine， and clarified the scientific connotation of the action mechanism and material basis of the herb pair Rhizoma Coptidis-Fructus Evodiae in the treatment of gastric cancer.

Wang et al.[10] conducted an in-vivo anticancer activity test by inhibiting the growth of S180 tumor to study the synergistic anticancer effect and mechanism of Zuojin Pill （ZJW）. His research found that Zuojin Pill could obviously induce apoptosis of cancer cells， and the principle might be related to the gene expression and activity of serum tumor markers.

Li et al.[11] observed the changes in the proliferation and apoptosis of colonic mucosal gland cells by morphological methods and found that the aqueous extracts of Rhizoma Coptidis and Fructus Evodiae could significantly inhibit the formation of aberrant crypt foci （ACF）， indicating that the water extract of Rhizoma Coptidis-Fructus Evodiae has certain inhibitory and clinical therapeutic effects on colon cancer， and its mechanism might be related to inhibiting the proliferation of colonic glands in the middle and distal segments of colon cancer and promoting cell apoptosis. Chou et al.[12] first demonstrated that Zuojin Pill significantly inhibited the growth of cancer cells in immunocompetent mice with HepG2 xenografts by establishing a human liver cancer xenograft model.

Cardiovascular diseases

Liu et al.[13] adopted the method of network pharmacology， and obtained 41 compounds， 212 potential target genes and 44 major signaling pathways based on two important parameters of oral bioavailability （OB≥30%） and drug-like properties （DL≥0.18） through the TCMSP database. Among the 44 major signaling pathways， 30 pathways are related to cancer， 7 pathways are related to cardiovascular and cerebrovascular diseases， and 7 pathways are involved in both cancer and cardiovascular and cerebrovascular diseases. The conclusions showed that the active ingredients of Rhizoma Coptidis-Fructus Evodiae produce an anti-cancer effect by up-regulating the expression of cancer apoptotic genes and down-regulating the expression of cell cycle and anti-apoptosis-related genes through multiple components， multiple targets and multiple pathways， and achieve the effect of treating cardiovascular and cerebrovascular diseases by inhibiting vascular calcification， protecting vascular cells and inhibiting cell apoptosis and proliferation.

Antioxidant and antimicrobial effects

Some studies have found that Zuojin Pill， Ganlu Powder， Zhuyu Pill， and Fanzuojin Pill have a strong inhibitory effect on the activity of Staphylococcus aureus and have a scavenging effect on free radicals in the classic compatibility series of Rhizoma Coptidis and Fructus Evodiae. It is speculated that the antimicrobial effect is related to the content of total alkaloids of Rhizoma Coptidis， and the antioxidant capacity is related to the content of drug active substances[14].

Antidepressant

According to the statistics of the WTO， in the proportions of various diseases in the world， the incidence of depression is about one tenth of all disease types， and depression has become the fourth largest disease in the world. It is estimated that it will become the second largest disease following heart disease by 2020. The incidence of depression in China is about 3%-5%， and more than 26 million people have been affected[15].

Drugs for the treatment of depression are currently mainly monomeric chemical drugs. Chemical drugs have the advantages of clear curative effect and treatment of specific target sites， but they have many adverse reactions， such as： addiction， easy relapse， too narrow efficacy curve and too long half-life. Therefore， scientists have turned their attention to the field of botanical medicine， especially the research and development of safe and effective antidepressants from traditional Chinese herbal medicines， which has become a hot spot in the current medical community[16]. Rhizoma Coptidis has the functions of easing mental anxiety， clearing away heat and drying dampness. Clinically， Rhizoma Coptidis is often used as the main medicine in the treatment of insomnia. The basic theory of traditional Chinese medicine believes that the mind is the master of the gods， and when the heat disturbs the mind， there are often depression， insomnia and other symptoms， while Rhizoma Coptidis is bitter and cold in nature， can be used for purifying heart fire and eliminating heat vexation， and has the effects of helping sleep， soothing the liver and relieving depression[17].

Studies have shown that Rhizoma Coptidis has anti-anxiety effects. Peng et al.[18] investigated the antidepressant activity of berberine and found that berberine， the main component of Rhizoma Coptidis， has anxiolytic effects， and its mechanism of action was related to monoamine neurotransmitters and their metabolites， and serotonin （5-hydroxytryptamine） receptors. Guo et al.[19] observed the intervention effect of Rhizoma Coptidis on anxiety in mice through elevated plus maze and light-dark box experiments. They showed that Rhizoma Coptidis decoction had a certain anti-anxiety activity， and its anti-anxiety mechanism was related to the changes in the content of GABA in the brain of mice. Lee et al.[20] showed through research that Rhizoma Coptidis berberine had the effect of resisting morphine withdrawal-induced anxiety and depression， and the principle of action might be related to the overexpression of corticotropin-releasing hormone （CRF） and locus coeruleus tyrosine hydroxylase （TH） in the hypothalamus and the overexpression of brain-derived neuroinfluencing factor in the hippocampus induced by the reversal of morphine withdrawal.

Wang et al.[21] proved through research that the ethanol extract of Zuojin Pill had antidepressant effect， and its principle might be related to the central monoamine neurotransmitter system， in which 5-HT played a major role.

Clinical Application of Rhizoma Coptidis-Fructus Evodiae

Although Rhizoma Coptidis and Fructus Evodiae are cold and hot in nature， respectively， both of them taste bitter， as their main chemical components all contain alkaloids， which can be used for inhibiting bacteria and fungi， inhibiting or killing viruses. After being mixed and processed， the medicinal properties of Rhizoma Coptidis and Fructus Evodiae tend to be gentle， and they are often used for treating gastrointestinal diseases， regulating the stability of intestinal flora， improving sleep quality， and improving symptoms of liver stagnation and spleen deficiency[22].

Gastrointestinal disease

Rhizoma Coptidis and Fructus Evodiae can be used to treat gastrointestinal diseases. Chen et al.[23] carried out an orthogonal design to compare prescription compatibility of nine groups of Wuji Wan composed of Rhizoma Coptidis， Fructus Evodiae and fried Radix Paeoniae Alba into and single ingredient of C. chinensis. They found that the metabolism of Rhizoma Coptidis components in the intestinal flora was positively correlated with Wuji Wan when compatibly used， and they appeared to be in a balanced relationship. In addition， different proportions of Radix Paeoniae Alba， Fructus Evodiae and fried Radix Paeoniae Alba also had certain effects on the metabolic rate of berberine and palmatine. Zhang et al.[24] used the technology combining bioinformatics and network pharmacology to analyze the drug pair Rhizoma Coptidis-Fructus Evodiae， so as to explore the potential targets and action mechanism of Rhizoma Coptidis-Fructus Evodiae for the treatment of gastritis. After screening in relevant databases， they obtained 8 potential active ingredients of Rhizoma Coptidis and 17 potential active ingredients of Fructus Evodiae， and the two had two active ingredients in common. Moreover， 79 targets were screened in the drug pair Rhizoma Coptidis-Fructus Evodiae， and 18 common target genes were obtained by intersection with gastritis targets， such as CASP3， VEGFA， EGFR， IL-6， MYC and CCND1. The main function of Rhizoma Coptidis-Fructus Evodiae in the treatment of gastritis is to combine various proteins with different functions， such as： protein phosphatase， activation of transcription factor receptors， cytokine receptors， apoptosis receptors and vascular endothelial growth factor receptors. The pathways involved include HIF-1 signaling pathway， tumor necrosis factor signaling pathway， as well as various cancer pathways and virus infection pathways. It can be seen that the combination of Rhizoma Coptidis and Fructus Evodiae in the treatment of gastritis uses a multi-pathway-combined synergistic approach.

Insomnia

Because of its bitter and cold nature， Rhizoma Coptidis is often used to clear away heat pathogens， and make fire poison settle and be excreted from the body， thereby improving the state of depression. It is often used in combination with other medicines to treat insomnia， such as Huanglian Ejiao Decoction， which is composed of five kinds of medicines： Rhizoma Coptidis， Radix Scutellariae， Paeonia lactiflora， Ejiao and Jizihuang. Although the medicine has little taste， its clinical effect is excellent， and it is highly praised by doctors. Its origin comes from Treatise on Febrile Diseases. Treatment of Shaoyin Disease based on Syndrome Differentiation， which states that "Shaoyin disease， if it occurs for more than two or three days， the patients are troubled and cannot lie down， and Huanglian Ejiao Decoction is used for it"[25].

Xu et al.[26] in the practice of clinical observation， randomly divided 118 patients with insomnia due to yin deficiency with effulgent fire， divided into two groups. Specifically， 60 cases in the observation group were treated with Huanglian Ejiao Decoction， and 58 cases in the control group were treated with Bailemian Capsules， and the course of treatment was 28 d. The clinical indicators and clinical efficacy were analyzed after treatment. The results showed that the effective rate of the treatment group was 85%， and the effective rate of the control group was 55%， which was statistically significant （P<0.05）. The treatment group was better than the control group in improving insomnia （P<0.05）. From this， it can be seen that Huanglian Ejiao Decoction has a definite curative effect on insomnia due to yin deficiency with effulgent fire.

Blood lipid lowering

Recent studies have found that the combination of Rhizoma Coptidis and Fructus Evodiae can reduce blood lipids in hyperlipidemic mice and has obvious pharmacological effects in inhibiting the absorption of cholesterol， which cannot be achieved by using Rhizoma Coptidis and Fructus Evodiae alone. This is due to that in the combination of Rhizoma Coptidis and Fructus Evodiae， Fructus Evodiae is used to diverge the grain of skin and the texture of the subcutaneous flesh， open the channels of the skin， and promote the uplifting of the skin， while the bitter cold of Rhizoma Coptidis is used to expel fiery heat， cleanse the stomach， and mainly plays a role of settling down. One is cold and the other is hot， and one rises and the other falls， which suggests that the scientific connotation contains in the equilibrium[27].

Conclusions

The application of Rhizoma Coptidis-Fructus Evodiae has a long history. As a relatively fixed combination of two herbs commonly used in traditional Chinese medicine， it is often used to treat various diseases caused by damp-heat accumulation in the liver and gallbladder， and the spleen and stomach， and the two kinds of medicines are opposite in nature but complement each other， and achieves a great effect based on simple medicines[28]. Now， the pharmacological effects and clinical efficacy of Rhizoma Coptidis have been fully studied. However， in terms of the action mechanism of the active ingredients in Rhizoma Coptidis-Fructus Evodiae， it involves a variety of monomers and active ingredients of traditional Chinese medicine[29]， while the research on the components of traditional Chinese medicine has a history of hundreds of years， and because of its complex components and huge system， it is extremely difficult to study the effects of traditional Chinese medicine on the body from the mixture system[30]. Therefore， there is still a certain research space for the study of drug pairs in the study of their metabolic components.

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