Eucommia folium can be prepared into tea with the ability to prevent and treat hyperuricemia

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In this study, a mouse HUA model was established via gavage of potassium oxonate and hypoxanthine, and this HUA model was treated with DZ to investigate the therapeutic effect of DZ on HUA. This study recruited 30 HUA volunteers, who drank 10 g of DZ daily for 4 consecutive weeks. The serum HUA levels of UA volunteers were measured once per week to observe the anti-HUA efficacy of DZ at the clinical level. Animal experiments have shown that DZ has therapeutic effects on HUA. DZ effectively reduces the levels of uric acid (UA), creatinine (Cr), and urea nitrogen (BUN) in the serum of HUA mice; decreases xanthine oxidase (XOD) activity in the serum; and alleviates damage to kidney tissues and glomeruli. Metabolomic analysis revealed that DZ affects multiple metabolites, such as orotidine, orotic acid, ureidosuccinic acid, 1-methylhistidine, and other metabolites, and these metabolites are involved mainly in pyrimidine metabolism, histidine metabolism, and riboflavin metabolism. Clinical research revealed that, after DZ was consumed, the UA levels in the HUA volunteers significantly decreased. DZ can prevent and treat HUA, and is in the same class of traditional Chinese medicines used in medicine and food, with extremely low toxicity and high safety. Therefore, DZ is suitable as a functional food for the prevention and treatment of HUA. Eucommia folium Hyperuricaemia Homology-of-medicine-and-food Functional food Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Introduction Eucommia ulmoides Oliver, a plant of the Eucommia genus in the Eucommia family, is a deciduous tree that can reach heights of up to 20 m [ 1 ]. The bark of Eucommia ulmoides Oliver can be used as a drug to treat arthritis, hypertension, diabetes and other diseases [ 2 – 5 ]. Although the bark of Eucommia ulmoides Oliver has good medicinal value, peeling it can cause serious damage to Eucommia ulmoides Oliver trees, and excessive peeling can lead to their death. In China, Eucommia ulmoides Oliver is a rare and endangered second-class protected plant, and the number of wild Eucommia ulmoides Oliver trees is low [ 6 ]. For sustainable development, this study aims to investigate the activity of Eucommia folium and develop products using leaves instead of bark as raw materials. The research team is located in Yantai, a coastal city in China. Owing to excessive seafood consumption, the incidence of hyperuricaemia is very high, which severely harms the health of local people [ 7 ]. Our research team reported that drinking Eucommia folium soaked in water can effectively reduce the uric acid (UA) levels among local people. At present, there are no reports on the effects of Eucommia folium on reducing UA. Therefore, this study aimed to investigate whether Eucommia folium has a reducing effect on UA and to develop it into a product for the prevention and control of HUA. In this study, we used purification, air drying, page cutting, withering, moisture regaining, drying, and aroma enhancement techniques to prepare Eucommia ulmoides leaves into a tea (abbreviation: DZ) and studied the anti-HUA effect of DZ in HUA model mice and HUA volunteers as experimental subjects. The results showed that DZ can effectively reduce UA levels in HUA volunteers and mice, alleviate kidney damage, and ameliorate metabolic disorders. These results indicate that DZ is suitable as a functional food with anti-HUA effects (Fig. 1 ). Materials and Methods Chemicals and materials Eucommia folium was purchased from Huayu Agricultural Development Co., Ltd. (Yantai, Shandong Province, China). The Uric Acid (UA) Content Assay Kit, Urea Nitrogen (BUN) Content Assay Kit, Creatinine (Cr) Content Assay Kit, and Xanthine Oxidase (XOD) Activity Assay Kit were purchased from Beijing Solarbio Science & Technology Co., Ltd. (Beijing, China). Potassium sulfonate (purity ≥ 99.0%) and hypoxanthine (purity ≥ 99.0%) were purchased from Beijing Solarbio Science & Technology Co., Ltd. (Beijing, China). Nontargeted metabolomics detection-related reagents were obtained from Beijing Solarbio Technology Co., Ltd. Untargeted metabolomics detection-related reagents were obtained from the Shenzhen Weike Meng Technology Group Co., Ltd. (Shenzhen, China). Preparation of DZ The preparation process for DZ is as follows: ① Picking: The suitable time for picking Eucommia folium leaves is approximately June 20th. Leaves that are mature, have full flesh and a dark green colour are chosen. When picking, the petioles are cut off, stacked neatly, and processed on site. Do not store them for too long. ② Purification: After entering the workshop, Eucommia folium should first be cleaned with clean water to remove the dust attached to the surface of the leaves. The cleaning requires rinsing twice with running tap water, without rubbing, to prevent damage to the leaves. ③ Air drying: The cleaned Eucommia folium leaves were dried with a fan. ④ Cut the pages: The cleaned Eucommia folium leaves were placed evenly into a leaf cutter and were cut into thin 0.5 cm strips. ⑤ Finish filming: The Eucommia folium leaves were cut into strips and sent to a dryer for withering. The withering temperature should be controlled at approximately 510 degrees Celsius. After withering, the leaves should be immediately cooled to the ambient temperature in a tracked air cooler to prevent residual heat from ripening and affecting the withering effect. ⑥ Returning tide: After withering and cooling, the Eucommia folium leaves should be placed in an open tea basket and left to settle for 4 hours to naturally regain moisture. ⑦ Drying. The rehydrated Eucommia folium leaves were placed into a dryer for drying, with a drying temperature controlled of approximately 180 degrees and not too high. This process was repeated 1–2 times. ⑧ Titian: Place the Eucommia folium leaves that have been dried twice into a tea stir fry machine and stir fry until they are semicharred. It is advisable to stir fry until there is an aroma overflow. ⑨ Sealing: After stir frying the Eucommia folium leaves , they were cooled thoroughly and stored in a sealed bag. ⑩ Chen Hua: Eucommia folium was placed in breathable cotton bags, which were then placed in an ageing workshop for natural temperature and humidity ageing treatment. The humidity should not exceed 60%. When the humidity is too high, attention should be given to dehumidification to prevent mould growth. ⑪ Fermentation: The aged Eucommia folium leaves are placed into a fermentation chamber for fermentation. ⑫ Compression moulding: A cake press is used to press the fermented Eucommia folium leaves into the desired shape to obtain the DZ. Preparation of the DZ water extract A total of 100 g of DZ was added to 5 L of distilled water for reflux extraction, and the mixture was extracted for 1 hour each time; this process was repeated twice. After extraction, the water extracts were combined and filtered with a 200-mesh filter cloth. The water extract was concentrated to 100 mL using a rotary evaporator. The concentrated solution was freeze dried into a powder and weighed. Finally, 15.37 g of powder was obtained, which was the DZ water extract, with an extraction rate of 15.73%. Animals and ethics statement A total of 50 adult male C57BL/6 mice (4 weeks old) were used in this study. All animals were purchased from Sibeifu (Beijing) Biotechnology Co., Ltd. Licence number: SCXK(jing)2019-0010. All the animals were kept in steel rodent cages, and the room temperature for the animals was controlled at 22 ± 2℃. The humidity was controlled at 60–80%, with a 12 h light:dark cycle (light period: 07:00–19:00; dark period: 19:00–07:00). The animal use protocol listed below was reviewed and approved by the Binzhou Medical University Institutional Animal Care and Use Committee (2023 − 198). Mouse HUA model A mouse HUA model was constructed by using a gavage of potassium oxonate (300 mg/kg) + hypoxanthine (500 mg/kg). Potassium oxonate was administered orally at a volume of 0.1 mL for 4 weeks, and a potassium oxonate solution was prepared by adding 3 g of potassium oxonate and 40 mL of 0.5% CMC-Na. Then, 0.1 mL of hypoxanthine was added by gavage for 4 weeks, and the hypoxanthine solution was prepared as follows: 5 g of hypoxanthine + 40 mL of 0.5% CMC-Na. Design of the animal experimental groups Fifty adult male C57BL/6 mice were randomly divided into 5 groups: the control group, HUA model group, 0.1 mg/kg DZ water extract group (DZ-L), 1 mg/kg DZ water extract group (DZ-M), and 10 mg/kg DZ water extract group (DZ-H). The treatment for each experimental group was as follows: in the control group, 0.25 mL of distilled water was orally administered for 4 weeks. For the HUA model group, 0.1 mL of potassium oxonate solution + 0.1 mL of hypoxanthine solution was administered by gavage. After 1 week, 0.1 mL of potassium oxonate solution + 0.1 mL of hypoxanthine solution + 0.05 mL of distilled water were added by gavage for 3 weeks. DZ-L group: gavage of 0.1 mL of potassium oxonate solution + 0.1 mL of hypoxanthine solution. After 1 week, 0.1 mL of potassium oxonate solution + 0.1 mL of hypoxanthine solution + 0.1 mg/kg DZ water extract were gavaged for 3 weeks. In the DZ-M group, 0.1 mL of potassium oxonate solution + 0.1 mL of hypoxanthine solution were gavaged. After 1 week, 0.1 mL of potassium oxonate solution + 0.1 mL of hypoxanthine solution + 1 mg/kg DZ water extract were gavaged for 3 weeks. In the DZ-H group, 0.1 mL of potassium oxonate solution + 0.1 mL of hypoxanthine solution were gavaged. After 1 week, 0.1 mL of potassium oxonate solution + 0.1 mL of hypoxanthine solution + 10 mg/kg DZ water extract were gavaged for 3 weeks. Biochemical index detection After the model was established, 1 mL of blood was taken from the mouse eyeball, left at room temperature for 2 h, centrifuged (3500 rpm) for 10 min, collected, packaged, and stored at -20℃ for future use. By strictly following the instructions of the UA, Cr, BUN, and XOD test kits, the UA, Cr, BUN, and XOD levels in the serum were determined. Detecting pathological damage to the kidneys and glomeruli After blood collection, the C57BL/6 mice were euthanized via the cervical dislocation method, and their livers were removed. The livers were washed with precooled physiological saline and dried with filter paper. The livers were then fixed with 4% neutral formaldehyde. HE-stained sections were used to observe pathological damage in renal tissue, whereas PAS-stained sections were used to observe pathological damage in glomeruli. Untargeted serum metabolomics detection Untargeted metabolomics analysis was performed on the serum of each group of mice using liquid chromatography‒mass spectrometry. After the model was established, 1 mL of blood was collected from the mouse eyeball, left at room temperature for 2 h, and centrifuged at 3500 rpm for 10 min, after which 150 µL of serum was collected. The serum was then sent to the Weike Meng Technology Company for untargeted metabolomics analysis. Case collection Patient source: Eighty patients with hyperuricaemia, who were admitted to the Affiliated Hospital of Binzhou Medical College from March 2023 to October 2023, including 40 males and 40 females aged between 40 and 65 years, were selected as the research group. Patient selection criteria: These criteria were developed on the basis of the American College of Rheumatology (ACR) gout classification criteria of 1977 and the ACR/EULAR gout classification criteria of 2015. The inclusion criteria for hyperuricaemia were as follows: (1) met the diagnostic criteria for hyperuricaemia, which means that the diagnostic criterion for hyperuricaemia was that the fasting blood uric acid levels were measured twice on different days, with levels > 420 µmol/L in males and levels > 360 µmol/L in females; (2) ages between 40 and 65 years, the sex of which is not limited; (3) acute onset, with a course of disease within 14 days; and (4) no gout symptoms have yet appeared. (5) All participants provided informed consent and signed an informed consent form. The exclusion criteria were as follows: not taking diuretics or medications to lower uric acid levels within 3 months; acute or chronic infections; hypertension; coronary heart disease; malignant tumours; liver and kidney diseases; diabetes; blood system diseases; abnormal liver and kidney function or gout; and pregnancy or lactation. The case dropout criteria were as follows: ① patients who experienced serious adverse events or complications and were not suitable for continued treatment; ② patients who had poor compliance; who used medication that did not reach 80% of the prescribed amount or exceeded 120% of the prescribed amount; ③ patients who voluntarily withdrew or were lost to follow-up during the treatment process; ④ patients who had not completed the entire course of treatment, which affected the efficacy or safety assessment; and ⑤ patients whose incomplete information affected the validity and safety of the judgement. Patient dropout treatment: ① After the subject falls off, the researcher should try to contact the subject as much as possible, inquire about the reasons, and complete the evaluation items as much as possible. ② The dropout cases are all required for the set of statistics to provide a full analysis, and dropout patients do not need to be supplemented separately. The termination test criteria were as follows: ① Those who experienced serious adverse events; ② during the course of the disease, the condition worsened, and ineffective cases were treated; ③ serious deviations occurred during the implementation of clinical trial protocols; and ④ the subjects requested to withdraw during the clinical trial process. DZ efficacy testing A total of 30 HUA volunteers, including 20 males and 10 females, were selected for this study. Volunteers drank DZ powder each day for 4 weeks, with a daily intake of 10 g. Weekly testing of serum UA levels in HUA volunteers was performed and serum UA levels were retested after discontinuing DZ for one month. Safety evaluation criteria According to the "Guidelines for Clinical Research of Traditional Chinese Medicine New Drugs (Trial)" published in 2002, the main focus of interest is the digestive disorders and abdominal pain of patients before and after treatment, as well as other adverse reactions, such as gastrointestinal discomfort, bloating, vomiting, diarrhoea, bloody stools, and black stools, and safety indicators, such as liver and kidney function. The degrees of symptoms were classified as follows: ① no adverse reactions; ② mild reactions were mild, short-lived, and tolerable; ③ moderate reactions were severe, stopped, and could be relieved without treatment; and ④ severe reactions, terminated, were symptomatic. Statistical analysis The data are presented as the means ± standard deviations from at least six independent experiments. Statistical differences were determined by using Student’s t-tests, where P < 0.05 was considered to indicate statistical significance. The analyses were performed via the Statistical Program for Social Sciences Software (International Business Machines Corporation, New York, USA). Results DZ reduces HUA in mice As shown in Fig. 2 , compared with those of the control group, the serum UA content, Cr content, BUN content, and XOD activity of the HUA group were significantly greater. Compared with the HUA group, the DZ groups presented significantly lower levels of UA, Cr, and BUN and XOD activity in the serum of HUA mice. DZ alleviates renal tissue damage in HUA mice As shown in Fig. 3 , the HE results revealed that the renal tissue cells of the mice in the control group were arranged neatly, with clear and full glomerular and tubular structures, uniform staining of tubular epithelial cells, and normal morphologies. In the renal tissues of HUA group mice, glomerular deformation and atrophy were observed, the renal tubules were dilated, and many vacuolar changes were observed in the cells. Compared with those in the HUA group, the renal tissue cells in the DZ groups were arranged neatly, with clear and full glomerular and tubular structures, uniform staining of tubular epithelial cells, and normal morphologies. DZ reduces glomerular injury in HUA mice As shown in Fig. 4 , the PAS staining results revealed that the glomerular structures of the mice in the control group were clear, full, and had normal morphologies. The glomeruli of mice in the HUA group exhibited thickening of the basement membrane. Compared with the HUA group, the mice in the DZ groups had clear and plump glomerular structures and normal morphologies. Effect of DZ on the metabolic levels of HUA mice The high-dose treatment had the best therapeutic effect among the three DZ treatment groups, so metabolomics analysis was conducted on the control group, HUA group, and DZ-H group. Fig. S1 shows the top 20 metabolites in terms of their contents, while the remaining metabolites are included in Others, indicating preliminary differences in metabolite compositions and structures among the groups. The results of heatmap clustering also preliminarily revealed differences in metabolite compositions and structures among the groups (Fig. S2). Using OPLS-DA and Q2 as the test statistic, the random distribution of Q2 is obtained via the permutation method. As shown in Fig. S3, when Q2 > 0.5 and P < 0.5, the model is appropriate and has significant predictive ability, indicating that there should be significant differences in metabolites between groups. The OPLS-DA point cloud map results revealed that the data from the control group, HUA group, and DZ-H group were separate, whereas the data within each group were closely aligned, indicating significant differences in the serum metabolite levels among the three groups of mice (Fig. 5 ). According to the variable importance in the projection (VIP) threshold generated by OPLS-DA processing, metabolites were screened and set to VIP > 1. The P value for significantly different metabolites was set to 0.05. In accordance with the above criteria, this study identified and selected the top 15 metabolites with significant differences through secondary mass spectrometry. HUA can cause increases or decreases in the contents of some metabolites, whereas DZ can reverse the changes in these metabolites that are caused by HUA (Fig. 6 and Fig. S4). MetaboAnalyst 5.0 ( https://www.metaboanalyst.ca/ ) was used to perform pathway analysis on the differentially abundant metabolites, and the results are shown in Fig. 7 . The above metabolites are involved in pyrimidine metabolism, histidine metabolism, and riboflavin metabolism. DZ reduces HA levels in HUA patients This study ultimately selected 30 HUA volunteers, including 20 males and 10 females. After taking DZ, the UA levels of all the volunteers decreased (Fig. 8 ). This result indicates that DZ can effectively reduce UA levels in patients with HUA. Results of network pharmacology analysis This study used network pharmacology techniques to preliminarily analyse the possible mechanism by which DZ prevents and treats HUA. A total of 862 HUA-related genes and 168 Eucommia folium targets were predicted from four databases: GeneCard, OMIM, DrugBank, and TTD. Sixty-five common targets of Eucommia folium and HUA were screened through Venn analysis (Fig. S5), and a PPI analysis network diagram was subsequently obtained through STRING prediction and Cytoscape network attribute topology calculations (Fig. S6). Sixty-five candidate targets were predicted using the TCMIP database, and a total of 18 Eucommia folium -related targets were obtained after removing duplicate values on the basis of the screening criterion of a similarity score ≥ 0.6. To evaluate the connectivity between the three compounds and their targets, Cytoscape v3.9.0 was used to construct a chemical target (C-T) network (Fig. S7). GO enrichment analysis of the potential targets of DZ for HUA was performed via the DAVID database. The top 20 biological process terms are shown in Fig. 9 . The figure shows that the most important items are response to lipids, response to oxygen-containing compounds, response to organic cyclic compounds, response to endogenous stimuli, regulation of apoptotic processes, and regulation of programmed cell death. KEGG pathway enrichment analysis was completed through the Metascape database. The top 20 pathways and their related gene targets are shown in Fig. 10 , among which human cytomegalovirus infection, the AGE-RAGE signalling pathway in diabetic complications, the IL-17 signalling pathway, Kaposi sarcoma-associated herpesvirus infection, and the TNF signalling pathway may all be involved in DZ therapy for HUA. Discussion HUA is a common metabolic disease seen in clinical practice that is caused by disorders in purine metabolism in the body. Under a normal purine diet, fasting blood UA levels increase twice on different days, with those of males exceeding 420 µmol/L and those of females exceeding 360 µmol/L, indicating HUA [ 8 , 9 ]. HUA is closely related to the occurrence and development of gout, kidney stones, cardiovascular and cerebrovascular diseases, type 2 diabetes, metabolic syndrome and other diseases, especially gout, and HUA is the main cause of gout [ 10 – 12 ]. The incidence of HUA has markedly increased by approximately 20% worldwide, and patients have become younger, which is concerning; thus, HUA has emerged as a public health challenge [ 13 , 14 ]. The overall prevalence rate of HUA in China is 13.3%, and the number of HUA patients is approximately 177 million. It has become the second most common metabolic disease after diabetes and poses a serious threat to the lives and health of the Chinese people [ 15 , 16 ]. Therefore, the development of safe and effective methods for HUA prevention and control is urgently needed. This study constructed an HUA mouse model by administering potassium oxonate and hypoxanthine via gavage, which increased the intake of high-purine foods and reduced uric acid excretion. The results revealed that the levels of UA, Cr, and BUN in the serum of the model mice were significantly increased, and severe damage was observed in both renal and glomerular tissues, which is consistent with the symptoms of HUA [ 17 ]. These results indicate that the HUA model in this study was successful. After the oral administration of the DZ water extract to HUA mice, the levels of UA, Cr, and BUN in the serum of HUA mice were significantly reduced, and the degree of damage to kidney and glomerular tissues was significantly reduced. These findings indicate that DZ can be used to treat HUA in mice and preliminarily suggest that DZ may have therapeutic effects on HUA. To further evaluate the anti-HUA effect of DZ, this study selected 30 HUA patients as experimental subjects. We observed that after drinking 10 g of DZ daily for 1 week, the serum UA levels of the HUA volunteers decreased. After drinking DZ daily for 4 weeks, the UA levels of most HUA volunteers decreased to within the normal range. These results once again indicate that DZ has the ability to prevent and treat HUA. Metabolomics is a research method that imitates the research ideas of genomics and proteomics, quantitatively analyses all metabolites in an organism, and searches for the relative relationships among metabolites and physiological and pathological changes. It is an integral part of systems biology [ 18 , 19 ]. Metabolomics can be used to study drug therapy for diseases at the overall metabolic level and has been widely used to investigate the pharmacological mechanisms of plants [ 20 , 21 ]. This study conducted serum metabolomics analysis on various groups of mice and revealed that DZ can reverse the disorders of pyrimidine metabolism, histidine metabolism, and riboflavin metabolism caused by HUA. Pyridine metabolism, histidine metabolism, and riboflavin metabolism are involved in purine metabolism and play important roles in the pathogenesis of HUA. These findings suggest that DZ may treat HUA by improving pyrimidine metabolism, histidine metabolism, and riboflavin metabolism. Conclusion Through in-depth research on Eucommia folium , it has been confirmed that it is nontoxic and very safe. In China, Eucommia folium is also recognized as a medicinal and edible plant that can be directly consumed as food [ 22 ]. This study used Eucommia folium as a single raw material and used a series of conventional physical methods to prepare a tea (DZ). The results of this study revealed that DZ significantly reduced the serum UA levels in HUA mice, and after HUA volunteers drank DZ, their serum UA contents decreased. These results suggest that DZ may have therapeutic effects on HUA. Therefore, it may be more suitable for the prevention and treatment of HUA, especially for the prevention of HUA. Limitations There are several limitations to this study. ① DZ water extract is a mixture, and the active ingredients for anti-HUA effects are not yet clear. ② This study lacked research on the mechanism of the anti-HUA effect of DZ. This study revealed decreased UA levels in HUA volunteers after they drank DZ, lacked a blank control group, and cannot directly prove that DZ has anti-HUA effects. Our team will gradually address these issues in future research. Declarations Funding Not applicable. Author information Qing Hao and Ying Liu contributed equally to this work. Author Contributions Jichun Han: Conceptualisation, Methodology, Data curation, Validation, Formal analysis, Investigation, Resources, Visualisation, Writing – original draft; Qing Hao, Ying Liu, Zikun Zhai, Bo Wang, Lin Jiang, and Qiusheng Zheng: Conceptualisation, Methodology, Validation, Formal analysis, Investigation, Resources, Visualisation, Writing – original draft; Jichun Han, Xiangcheng Fan, Jiawei Su, Maiting Zhang, and Jiajun Li: Conceptualisation, Validation, Writing – review and editing; Shuo Chen, Ziyun Ye, Qiusheng Zheng, and Xiangcheng Fan: Conceptualisation, Validation, Writing – review and editing, Supervision; JCH and Xiangcheng Fan: Investigation, Resources. Corresponding authors Correspondence to Jichun Han or Xiangcheng Fan. Supplementary Information The online version contains supplementary material available at Data Availability The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Ethical Approval Not Applicable. Consent for Publication Not Applicable. Consent to Participate Not Applicable. Conflicts of Interest/Competing Interests The authors declare no conflict of interest. Clinical Trial Number Not applicable. References Huang Q, Tan JB, Zeng XC et al (2021) Lignans and phenolic constituents from Eucommia ulmoides Oliver. Nat Prod Res 35:3376–3383. https://doi.org/10.1080/14786419.2019.1700250 Ahn HY, Cho JH, Nam D et al (2019) Efficacy and safety of Cortex Eucommiae (Eucommia ulmoides Oliver) extract in subjects with mild osteoarthritis: Study protocol for a 12-week, multicenter, randomized, double-blind, placebo-controlled trial. 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Proc Natl Acad Sci USA 116:52–57. https://doi.org/10.1073/pnas.1808950116 Zhang Q, Luo P, Chen J et al (2022) Dissection of Targeting Molecular Mechanisms of Aristolochic Acid-induced Nephrotoxicity via a Combined Deconvolution Strategy of Chemoproteomics and Metabolomics. Int J Biol Sci 18:2003–2017. https://doi.org/10.7150/ijbs.69618 Qin S, Xiao W, Zhou C et al (2022) Pseudomonas aeruginosa: pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics. Signal Transduct Target Ther 7:199. https://doi.org/10.1038/s41392-022-01056-1 Bao L, Sun Y, Wang J et al (2024) A review of plant gold Eucommia ulmoides Oliv.: A medicinal and food homologous plant with economic value and prospect. Heliyon 10:e24851. https://doi.org/10.1016/j.heliyon.2024.e24851 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5233926","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":365173499,"identity":"5ba7f761-dc2d-4ab6-a12f-9aff37997ffb","order_by":0,"name":"Qing Hao","email":"","orcid":"","institution":"Binzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qing","middleName":"","lastName":"Hao","suffix":""},{"id":365173500,"identity":"f205f27b-1448-4483-a1fb-9308ebfb9234","order_by":1,"name":"Ying Liu","email":"","orcid":"","institution":"Binzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Liu","suffix":""},{"id":365173501,"identity":"070f0eae-5b51-4ec4-b51a-1ab520d3cc9c","order_by":2,"name":"Zikun Zhai","email":"","orcid":"","institution":"Binzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zikun","middleName":"","lastName":"Zhai","suffix":""},{"id":365173502,"identity":"85f472ba-404e-4710-a93f-92b87053db45","order_by":3,"name":"Bo Wang","email":"","orcid":"","institution":"Qilu Medical University","correspondingAuthor":false,"prefix":"","firstName":"Bo","middleName":"","lastName":"Wang","suffix":""},{"id":365173503,"identity":"69d2d5c9-7376-417b-807f-034b60075790","order_by":4,"name":"Lin Jiang","email":"","orcid":"","institution":"Binzhou Medical 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University","correspondingAuthor":false,"prefix":"","firstName":"Ziyun","middleName":"","lastName":"Ye","suffix":""},{"id":365173514,"identity":"a743523a-bf56-4253-bf59-44dffe6851c2","order_by":11,"name":"Qiusheng Zheng","email":"","orcid":"","institution":"Binzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qiusheng","middleName":"","lastName":"Zheng","suffix":""},{"id":365173515,"identity":"8267dc21-a089-488e-bbeb-37ca5a09d373","order_by":12,"name":"Xiangcheng Fan","email":"","orcid":"","institution":"International Institutes of Medicine, Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Xiangcheng","middleName":"","lastName":"Fan","suffix":""},{"id":365173516,"identity":"60b72fac-9486-4a11-b99f-6888e611b5f3","order_by":13,"name":"Jichun Han","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYBACfvb2Awc+/LCRY2NvIFKLZM+ZxIcze9KM+XgOEKnF4EaCsTEP26HEeRIJxGo5kJAmwcNzwJhN8vHGGww1NtGEHXbg4DEJCYs7cmzSacUWDMfSchsIaeE72JAmYcDzzJhNOsdMgrHhMGEtDIcZzCQS2A4ntkmeIVKLwDEGY4MDIC0SPERqkezhSXzYCAxkNh6gXxKI8Qu//PMDh/8Ao1K+/fDGGx9qbIjwCxIwIDpqkLSQqmMUjIJRMApGBgAAfGZBZuBGKZwAAAAASUVORK5CYII=","orcid":"","institution":"Binzhou Medical University","correspondingAuthor":true,"prefix":"","firstName":"Jichun","middleName":"","lastName":"Han","suffix":""}],"badges":[],"createdAt":"2024-10-09 15:53:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5233926/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5233926/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":68091758,"identity":"887b38a3-7afa-468e-af0e-1515696b6534","added_by":"auto","created_at":"2024-11-02 18:12:40","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":57440,"visible":true,"origin":"","legend":"\u003cp\u003eGraphical abstract.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5233926/v1/87cae07262f619fa258455cd.jpg"},{"id":68091759,"identity":"5a2b51ac-7a19-4618-985e-21f5feecc5bd","added_by":"auto","created_at":"2024-11-02 18:12:40","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":55820,"visible":true,"origin":"","legend":"\u003cp\u003eDZ significantly reduced the levels of UA (A), Cr (B), BUN (C), and XOD activity (D) in the serum of HUA mice. Note: Note: \u003csup\u003e##\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01 compared to the control group; \u003csup\u003e**\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01 compared to the HUA group.\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5233926/v1/8f2d0080c640035a361a518d.jpg"},{"id":68091765,"identity":"22957972-dcac-43dc-a0b2-7d30af3f2c72","added_by":"auto","created_at":"2024-11-02 18:12:40","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":244659,"visible":true,"origin":"","legend":"\u003cp\u003eHE staining results showed that DZ reduced renal tissue damage in HUA mice.\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5233926/v1/144356266d86b77c569df97c.jpg"},{"id":68091761,"identity":"7bc86a8e-0bb2-4311-b127-21c02231436e","added_by":"auto","created_at":"2024-11-02 18:12:40","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":244539,"visible":true,"origin":"","legend":"\u003cp\u003ePAS staining results showed that DZ alleviated glomerular injury in HUA mice.\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5233926/v1/5527e1158dc852f01ca219ef.jpg"},{"id":68091804,"identity":"a75e828f-bcd9-474b-a50c-872ed01b0ea3","added_by":"auto","created_at":"2024-11-02 18:20:40","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":89103,"visible":true,"origin":"","legend":"\u003cp\u003eOPLS-DA point cloud map.\u003c/p\u003e","description":"","filename":"Picture5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5233926/v1/a31a691d50ce4992ba7c805c.jpg"},{"id":68091768,"identity":"6d0aa181-374b-45c6-916a-0f128735db61","added_by":"auto","created_at":"2024-11-02 18:12:40","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":95896,"visible":true,"origin":"","legend":"\u003cp\u003eOPLS-DA metabolite importance map.\u003c/p\u003e","description":"","filename":"Picture6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5233926/v1/274abdaa21260aac20ff956d.jpg"},{"id":68091764,"identity":"bf154802-6c45-4cd9-8e79-7ee81996feea","added_by":"auto","created_at":"2024-11-02 18:12:40","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":41529,"visible":true,"origin":"","legend":"\u003cp\u003eMetaboAnalyst 5.0 performed pathway analysis on differential metabolites, resulting in a bubble chart.\u003c/p\u003e","description":"","filename":"Picture7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5233926/v1/e2e4594251433d204060efd9.jpg"},{"id":68091803,"identity":"84678b2a-068b-4031-9085-2b376e3687f7","added_by":"auto","created_at":"2024-11-02 18:20:40","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":61484,"visible":true,"origin":"","legend":"\u003cp\u003eDZ reduces UA levels in the serum of HUA volunteers.\u003c/p\u003e","description":"","filename":"Picture8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5233926/v1/41a718cc93dcabb8b96ae3b5.jpg"},{"id":68091767,"identity":"93259d12-d1a1-47f8-8a85-8816fe2031b2","added_by":"auto","created_at":"2024-11-02 18:12:40","extension":"jpg","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":44831,"visible":true,"origin":"","legend":"\u003cp\u003eGO enrichment analysis - top 20 of GO terms enrichment.\u003c/p\u003e","description":"","filename":"Picture9.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5233926/v1/734949440723f12b2879fc8a.jpg"},{"id":68091766,"identity":"1cc19d75-d3a5-44ba-8935-8a2249aa1084","added_by":"auto","created_at":"2024-11-02 18:12:40","extension":"jpg","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":24194,"visible":true,"origin":"","legend":"\u003cp\u003eKEGG enrichment analysis - top 20 of pathway enrichment.\u003c/p\u003e","description":"","filename":"Picture10.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5233926/v1/55bea74ebd82552e2f2ff4ef.jpg"},{"id":68092037,"identity":"829d0de4-ceaf-433c-a492-83d3dad19c9c","added_by":"auto","created_at":"2024-11-02 18:28:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1494548,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5233926/v1/13dfc523-4995-482e-9fa1-8e8804be100e.pdf"},{"id":68091762,"identity":"ddbefbe5-c2f7-487f-aabb-760e7506aaf3","added_by":"auto","created_at":"2024-11-02 18:12:40","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":697746,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-5233926/v1/99cd09184fad34c4d87f6550.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Eucommia folium can be prepared into tea with the ability to prevent and treat hyperuricemia","fulltext":[{"header":"Introduction","content":"\u003cp\u003e \u003cem\u003eEucommia ulmoides\u003c/em\u003e Oliver, a plant of the Eucommia genus in the Eucommia family, is a deciduous tree that can reach heights of up to 20 m [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The bark of \u003cem\u003eEucommia ulmoides\u003c/em\u003e Oliver can be used as a drug to treat arthritis, hypertension, diabetes and other diseases [\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Although the bark of \u003cem\u003eEucommia ulmoides\u003c/em\u003e Oliver has good medicinal value, peeling it can cause serious damage to \u003cem\u003eEucommia ulmoides\u003c/em\u003e Oliver trees, and excessive peeling can lead to their death. In China, \u003cem\u003eEucommia ulmoides\u003c/em\u003e Oliver is a rare and endangered second-class protected plant, and the number of wild \u003cem\u003eEucommia ulmoides\u003c/em\u003e Oliver trees is low [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. For sustainable development, this study aims to investigate the activity of \u003cem\u003eEucommia folium\u003c/em\u003e and develop products using leaves instead of bark as raw materials.\u003c/p\u003e \u003cp\u003eThe research team is located in Yantai, a coastal city in China. Owing to excessive seafood consumption, the incidence of hyperuricaemia is very high, which severely harms the health of local people [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Our research team reported that drinking \u003cem\u003eEucommia folium\u003c/em\u003e soaked in water can effectively reduce the uric acid (UA) levels among local people. At present, there are no reports on the effects of \u003cem\u003eEucommia folium\u003c/em\u003e on reducing UA. Therefore, this study aimed to investigate whether \u003cem\u003eEucommia folium\u003c/em\u003e has a reducing effect on UA and to develop it into a product for the prevention and control of HUA.\u003c/p\u003e \u003cp\u003eIn this study, we used purification, air drying, page cutting, withering, moisture regaining, drying, and aroma enhancement techniques to prepare \u003cem\u003eEucommia ulmoides\u003c/em\u003e leaves into a tea (abbreviation: DZ) and studied the anti-HUA effect of DZ in HUA model mice and HUA volunteers as experimental subjects. The results showed that DZ can effectively reduce UA levels in HUA volunteers and mice, alleviate kidney damage, and ameliorate metabolic disorders. These results indicate that DZ is suitable as a functional food with anti-HUA effects (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eChemicals and materials\u003c/h2\u003e \u003cp\u003e \u003cem\u003eEucommia folium\u003c/em\u003e was purchased from Huayu Agricultural Development Co., Ltd. (Yantai, Shandong Province, China). The Uric Acid (UA) Content Assay Kit, Urea Nitrogen (BUN) Content Assay Kit, Creatinine (Cr) Content Assay Kit, and Xanthine Oxidase (XOD) Activity Assay Kit were purchased from Beijing Solarbio Science \u0026amp; Technology Co., Ltd. (Beijing, China). Potassium sulfonate (purity\u0026thinsp;\u0026ge;\u0026thinsp;99.0%) and hypoxanthine (purity\u0026thinsp;\u0026ge;\u0026thinsp;99.0%) were purchased from Beijing Solarbio Science \u0026amp; Technology Co., Ltd. (Beijing, China). Nontargeted metabolomics detection-related reagents were obtained from Beijing Solarbio Technology Co., Ltd. Untargeted metabolomics detection-related reagents were obtained from the Shenzhen Weike Meng Technology Group Co., Ltd. (Shenzhen, China).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePreparation of DZ\u003c/h3\u003e\n\u003cp\u003eThe preparation process for DZ is as follows: ① Picking: The suitable time for picking \u003cem\u003eEucommia folium\u003c/em\u003e leaves is approximately June 20th. Leaves that are mature, have full flesh and a dark green colour are chosen. When picking, the petioles are cut off, stacked neatly, and processed on site. Do not store them for too long. ② Purification: After entering the workshop, \u003cem\u003eEucommia folium\u003c/em\u003e should first be cleaned with clean water to remove the dust attached to the surface of the leaves. The cleaning requires rinsing twice with running tap water, without rubbing, to prevent damage to the leaves. ③ Air drying: The cleaned \u003cem\u003eEucommia folium\u003c/em\u003e leaves were dried with a fan. ④ Cut the pages: The cleaned \u003cem\u003eEucommia folium\u003c/em\u003e leaves were placed evenly into a leaf cutter and were cut into thin 0.5 cm strips. ⑤ Finish filming: The \u003cem\u003eEucommia folium\u003c/em\u003e leaves were cut into strips and sent to a dryer for withering. The withering temperature should be controlled at approximately 510 degrees Celsius. After withering, the leaves should be immediately cooled to the ambient temperature in a tracked air cooler to prevent residual heat from ripening and affecting the withering effect. ⑥ Returning tide: After withering and cooling, the \u003cem\u003eEucommia folium\u003c/em\u003e leaves should be placed in an open tea basket and left to settle for 4 hours to naturally regain moisture. ⑦ Drying. The rehydrated \u003cem\u003eEucommia folium\u003c/em\u003e leaves were placed into a dryer for drying, with a drying temperature controlled of approximately 180 degrees and not too high. This process was repeated 1\u0026ndash;2 times. ⑧ Titian: Place the \u003cem\u003eEucommia folium\u003c/em\u003e leaves that have been dried twice into a tea stir fry machine and stir fry until they are semicharred. It is advisable to stir fry until there is an aroma overflow. ⑨ Sealing: After stir frying the \u003cem\u003eEucommia folium leaves\u003c/em\u003e, they were cooled thoroughly and stored in a sealed bag. ⑩ Chen Hua: \u003cem\u003eEucommia folium\u003c/em\u003e was placed in breathable cotton bags, which were then placed in an ageing workshop for natural temperature and humidity ageing treatment. The humidity should not exceed 60%. When the humidity is too high, attention should be given to dehumidification to prevent mould growth. ⑪ Fermentation: The aged \u003cem\u003eEucommia folium\u003c/em\u003e leaves are placed into a fermentation chamber for fermentation. ⑫ Compression moulding: A cake press is used to press the fermented \u003cem\u003eEucommia folium\u003c/em\u003e leaves into the desired shape to obtain the DZ.\u003c/p\u003e\n\u003ch3\u003ePreparation of the DZ water extract\u003c/h3\u003e\n\u003cp\u003eA total of 100 g of DZ was added to 5 L of distilled water for reflux extraction, and the mixture was extracted for 1 hour each time; this process was repeated twice. After extraction, the water extracts were combined and filtered with a 200-mesh filter cloth. The water extract was concentrated to 100 mL using a rotary evaporator. The concentrated solution was freeze dried into a powder and weighed. Finally, 15.37 g of powder was obtained, which was the DZ water extract, with an extraction rate of 15.73%.\u003c/p\u003e\n\u003ch3\u003eAnimals and ethics statement\u003c/h3\u003e\n\u003cp\u003eA total of 50 adult male C57BL/6 mice (4 weeks old) were used in this study. All animals were purchased from Sibeifu (Beijing) Biotechnology Co., Ltd. Licence number: SCXK(jing)2019-0010. All the animals were kept in steel rodent cages, and the room temperature for the animals was controlled at 22\u0026thinsp;\u0026plusmn;\u0026thinsp;2℃. The humidity was controlled at 60\u0026ndash;80%, with a 12 h light:dark cycle (light period: 07:00\u0026ndash;19:00; dark period: 19:00\u0026ndash;07:00). The animal use protocol listed below was reviewed and approved by the Binzhou Medical University Institutional Animal Care and Use Committee (2023\u0026thinsp;\u0026minus;\u0026thinsp;198).\u003c/p\u003e\n\u003ch3\u003eMouse HUA model\u003c/h3\u003e\n\u003cp\u003eA mouse HUA model was constructed by using a gavage of potassium oxonate (300 mg/kg)\u0026thinsp;+\u0026thinsp;hypoxanthine (500 mg/kg). Potassium oxonate was administered orally at a volume of 0.1 mL for 4 weeks, and a potassium oxonate solution was prepared by adding 3 g of potassium oxonate and 40 mL of 0.5% CMC-Na. Then, 0.1 mL of hypoxanthine was added by gavage for 4 weeks, and the hypoxanthine solution was prepared as follows: 5 g of hypoxanthine\u0026thinsp;+\u0026thinsp;40 mL of 0.5% CMC-Na.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eDesign of the animal experimental groups\u003c/h2\u003e \u003cp\u003eFifty adult male C57BL/6 mice were randomly divided into 5 groups: the control group, HUA model group, 0.1 mg/kg DZ water extract group (DZ-L), 1 mg/kg DZ water extract group (DZ-M), and 10 mg/kg DZ water extract group (DZ-H). The treatment for each experimental group was as follows: in the control group, 0.25 mL of distilled water was orally administered for 4 weeks. For the HUA model group, 0.1 mL of potassium oxonate solution\u0026thinsp;+\u0026thinsp;0.1 mL of hypoxanthine solution was administered by gavage. After 1 week, 0.1 mL of potassium oxonate solution\u0026thinsp;+\u0026thinsp;0.1 mL of hypoxanthine solution\u0026thinsp;+\u0026thinsp;0.05 mL of distilled water were added by gavage for 3 weeks. DZ-L group: gavage of 0.1 mL of potassium oxonate solution\u0026thinsp;+\u0026thinsp;0.1 mL of hypoxanthine solution. After 1 week, 0.1 mL of potassium oxonate solution\u0026thinsp;+\u0026thinsp;0.1 mL of hypoxanthine solution\u0026thinsp;+\u0026thinsp;0.1 mg/kg DZ water extract were gavaged for 3 weeks. In the DZ-M group, 0.1 mL of potassium oxonate solution\u0026thinsp;+\u0026thinsp;0.1 mL of hypoxanthine solution were gavaged. After 1 week, 0.1 mL of potassium oxonate solution\u0026thinsp;+\u0026thinsp;0.1 mL of hypoxanthine solution\u0026thinsp;+\u0026thinsp;1 mg/kg DZ water extract were gavaged for 3 weeks. In the DZ-H group, 0.1 mL of potassium oxonate solution\u0026thinsp;+\u0026thinsp;0.1 mL of hypoxanthine solution were gavaged. After 1 week, 0.1 mL of potassium oxonate solution\u0026thinsp;+\u0026thinsp;0.1 mL of hypoxanthine solution\u0026thinsp;+\u0026thinsp;10 mg/kg DZ water extract were gavaged for 3 weeks.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eBiochemical index detection\u003c/h3\u003e\n\u003cp\u003eAfter the model was established, 1 mL of blood was taken from the mouse eyeball, left at room temperature for 2 h, centrifuged (3500 rpm) for 10 min, collected, packaged, and stored at -20℃ for future use. By strictly following the instructions of the UA, Cr, BUN, and XOD test kits, the UA, Cr, BUN, and XOD levels in the serum were determined.\u003c/p\u003e\n\u003ch3\u003eDetecting pathological damage to the kidneys and glomeruli\u003c/h3\u003e\n\u003cp\u003eAfter blood collection, the C57BL/6 mice were euthanized via the cervical dislocation method, and their livers were removed. The livers were washed with precooled physiological saline and dried with filter paper. The livers were then fixed with 4% neutral formaldehyde. HE-stained sections were used to observe pathological damage in renal tissue, whereas PAS-stained sections were used to observe pathological damage in glomeruli.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eUntargeted serum metabolomics detection\u003c/h2\u003e \u003cp\u003eUntargeted metabolomics analysis was performed on the serum of each group of mice using liquid chromatography‒mass spectrometry. After the model was established, 1 mL of blood was collected from the mouse eyeball, left at room temperature for 2 h, and centrifuged at 3500 rpm for 10 min, after which 150 \u0026micro;L of serum was collected. The serum was then sent to the Weike Meng Technology Company for untargeted metabolomics analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eCase collection\u003c/h2\u003e \u003cp\u003ePatient source: Eighty patients with hyperuricaemia, who were admitted to the Affiliated Hospital of Binzhou Medical College from March 2023 to October 2023, including 40 males and 40 females aged between 40 and 65 years, were selected as the research group.\u003c/p\u003e \u003cp\u003ePatient selection criteria: These criteria were developed on the basis of the American College of Rheumatology (ACR) gout classification criteria of 1977 and the ACR/EULAR gout classification criteria of 2015.\u003c/p\u003e \u003cp\u003eThe inclusion criteria for hyperuricaemia were as follows: (1) met the diagnostic criteria for hyperuricaemia, which means that the diagnostic criterion for hyperuricaemia was that the fasting blood uric acid levels were measured twice on different days, with levels\u0026thinsp;\u0026gt;\u0026thinsp;420 \u0026micro;mol/L in males and levels\u0026thinsp;\u0026gt;\u0026thinsp;360 \u0026micro;mol/L in females; (2) ages between 40 and 65 years, the sex of which is not limited; (3) acute onset, with a course of disease within 14 days; and (4) no gout symptoms have yet appeared. (5) All participants provided informed consent and signed an informed consent form.\u003c/p\u003e \u003cp\u003eThe exclusion criteria were as follows: not taking diuretics or medications to lower uric acid levels within 3 months; acute or chronic infections; hypertension; coronary heart disease; malignant tumours; liver and kidney diseases; diabetes; blood system diseases; abnormal liver and kidney function or gout; and pregnancy or lactation.\u003c/p\u003e \u003cp\u003eThe case dropout criteria were as follows: ① patients who experienced serious adverse events or complications and were not suitable for continued treatment; ② patients who had poor compliance; who used medication that did not reach 80% of the prescribed amount or exceeded 120% of the prescribed amount; ③ patients who voluntarily withdrew or were lost to follow-up during the treatment process; ④ patients who had not completed the entire course of treatment, which affected the efficacy or safety assessment; and ⑤ patients whose incomplete information affected the validity and safety of the judgement.\u003c/p\u003e \u003cp\u003ePatient dropout treatment: ① After the subject falls off, the researcher should try to contact the subject as much as possible, inquire about the reasons, and complete the evaluation items as much as possible. ② The dropout cases are all required for the set of statistics to provide a full analysis, and dropout patients do not need to be supplemented separately.\u003c/p\u003e \u003cp\u003eThe termination test criteria were as follows: ① Those who experienced serious adverse events; ② during the course of the disease, the condition worsened, and ineffective cases were treated; ③ serious deviations occurred during the implementation of clinical trial protocols; and ④ the subjects requested to withdraw during the clinical trial process.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eDZ efficacy testing\u003c/h2\u003e \u003cp\u003eA total of 30 HUA volunteers, including 20 males and 10 females, were selected for this study. Volunteers drank DZ powder each day for 4 weeks, with a daily intake of 10 g. Weekly testing of serum UA levels in HUA volunteers was performed and serum UA levels were retested after discontinuing DZ for one month.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSafety evaluation criteria\u003c/h2\u003e \u003cp\u003eAccording to the \"Guidelines for Clinical Research of Traditional Chinese Medicine New Drugs (Trial)\" published in 2002, the main focus of interest is the digestive disorders and abdominal pain of patients before and after treatment, as well as other adverse reactions, such as gastrointestinal discomfort, bloating, vomiting, diarrhoea, bloody stools, and black stools, and safety indicators, such as liver and kidney function. The degrees of symptoms were classified as follows: ① no adverse reactions; ② mild reactions were mild, short-lived, and tolerable; ③ moderate reactions were severe, stopped, and could be relieved without treatment; and ④ severe reactions, terminated, were symptomatic.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe data are presented as the means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations from at least six independent experiments. Statistical differences were determined by using Student\u0026rsquo;s t-tests, where \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to indicate statistical significance. The analyses were performed via the Statistical Program for Social Sciences Software (International Business Machines Corporation, New York, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eDZ reduces HUA in mice\u003c/h2\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, compared with those of the control group, the serum UA content, Cr content, BUN content, and XOD activity of the HUA group were significantly greater. Compared with the HUA group, the DZ groups presented significantly lower levels of UA, Cr, and BUN and XOD activity in the serum of HUA mice.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eDZ alleviates renal tissue damage in HUA mice\u003c/h2\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, the HE results revealed that the renal tissue cells of the mice in the control group were arranged neatly, with clear and full glomerular and tubular structures, uniform staining of tubular epithelial cells, and normal morphologies. In the renal tissues of HUA group mice, glomerular deformation and atrophy were observed, the renal tubules were dilated, and many vacuolar changes were observed in the cells. Compared with those in the HUA group, the renal tissue cells in the DZ groups were arranged neatly, with clear and full glomerular and tubular structures, uniform staining of tubular epithelial cells, and normal morphologies.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eDZ reduces glomerular injury in HUA mice\u003c/h2\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, the PAS staining results revealed that the glomerular structures of the mice in the control group were clear, full, and had normal morphologies. The glomeruli of mice in the HUA group exhibited thickening of the basement membrane. Compared with the HUA group, the mice in the DZ groups had clear and plump glomerular structures and normal morphologies.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eEffect of DZ on the metabolic levels of HUA mice\u003c/h2\u003e \u003cp\u003eThe high-dose treatment had the best therapeutic effect among the three DZ treatment groups, so metabolomics analysis was conducted on the control group, HUA group, and DZ-H group. Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e shows the top 20 metabolites in terms of their contents, while the remaining metabolites are included in Others, indicating preliminary differences in metabolite compositions and structures among the groups. The results of heatmap clustering also preliminarily revealed differences in metabolite compositions and structures among the groups (Fig. S2). Using OPLS-DA and Q2 as the test statistic, the random distribution of Q2 is obtained via the permutation method. As shown in Fig. S3, when Q2\u0026thinsp;\u0026gt;\u0026thinsp;0.5 and P\u0026thinsp;\u0026lt;\u0026thinsp;0.5, the model is appropriate and has significant predictive ability, indicating that there should be significant differences in metabolites between groups. The OPLS-DA point cloud map results revealed that the data from the control group, HUA group, and DZ-H group were separate, whereas the data within each group were closely aligned, indicating significant differences in the serum metabolite levels among the three groups of mice (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). According to the variable importance in the projection (VIP) threshold generated by OPLS-DA processing, metabolites were screened and set to VIP\u0026thinsp;\u0026gt;\u0026thinsp;1. The P value for significantly different metabolites was set to 0.05. In accordance with the above criteria, this study identified and selected the top 15 metabolites with significant differences through secondary mass spectrometry. HUA can cause increases or decreases in the contents of some metabolites, whereas DZ can reverse the changes in these metabolites that are caused by HUA (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e and Fig. S4). MetaboAnalyst 5.0 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.metaboanalyst.ca/\u003c/span\u003e\u003cspan address=\"https://www.metaboanalyst.ca/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) was used to perform pathway analysis on the differentially abundant metabolites, and the results are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e. The above metabolites are involved in pyrimidine metabolism, histidine metabolism, and riboflavin metabolism.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eDZ reduces HA levels in HUA patients\u003c/h2\u003e \u003cp\u003eThis study ultimately selected 30 HUA volunteers, including 20 males and 10 females. After taking DZ, the UA levels of all the volunteers decreased (Fig.\u0026nbsp;\u003cspan refid=\"Fig12\" class=\"InternalRef\"\u003e8\u003c/span\u003e). This result indicates that DZ can effectively reduce UA levels in patients with HUA.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eResults of network pharmacology analysis\u003c/h2\u003e \u003cp\u003eThis study used network pharmacology techniques to preliminarily analyse the possible mechanism by which DZ prevents and treats HUA. A total of 862 HUA-related genes and 168 \u003cem\u003eEucommia folium\u003c/em\u003e targets were predicted from four databases: GeneCard, OMIM, DrugBank, and TTD. Sixty-five common targets of \u003cem\u003eEucommia folium\u003c/em\u003e and HUA were screened through Venn analysis (Fig. S5), and a PPI analysis network diagram was subsequently obtained through STRING prediction and Cytoscape network attribute topology calculations (Fig. S6). Sixty-five candidate targets were predicted using the TCMIP database, and a total of 18 \u003cem\u003eEucommia folium\u003c/em\u003e-related targets were obtained after removing duplicate values on the basis of the screening criterion of a similarity score\u0026thinsp;\u0026ge;\u0026thinsp;0.6. To evaluate the connectivity between the three compounds and their targets, Cytoscape v3.9.0 was used to construct a chemical target (C-T) network (Fig. S7). GO enrichment analysis of the potential targets of DZ for HUA was performed via the DAVID database. The top 20 biological process terms are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig13\" class=\"InternalRef\"\u003e9\u003c/span\u003e. The figure shows that the most important items are response to lipids, response to oxygen-containing compounds, response to organic cyclic compounds, response to endogenous stimuli, regulation of apoptotic processes, and regulation of programmed cell death. KEGG pathway enrichment analysis was completed through the Metascape database. The top 20 pathways and their related gene targets are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig14\" class=\"InternalRef\"\u003e10\u003c/span\u003e, among which human cytomegalovirus infection, the AGE-RAGE signalling pathway in diabetic complications, the IL-17 signalling pathway, Kaposi sarcoma-associated herpesvirus infection, and the TNF signalling pathway may all be involved in DZ therapy for HUA.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eHUA is a common metabolic disease seen in clinical practice that is caused by disorders in purine metabolism in the body. Under a normal purine diet, fasting blood UA levels increase twice on different days, with those of males exceeding 420 \u0026micro;mol/L and those of females exceeding 360 \u0026micro;mol/L, indicating HUA [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. HUA is closely related to the occurrence and development of gout, kidney stones, cardiovascular and cerebrovascular diseases, type 2 diabetes, metabolic syndrome and other diseases, especially gout, and HUA is the main cause of gout [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The incidence of HUA has markedly increased by approximately 20% worldwide, and patients have become younger, which is concerning; thus, HUA has emerged as a public health challenge [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The overall prevalence rate of HUA in China is 13.3%, and the number of HUA patients is approximately 177\u0026nbsp;million. It has become the second most common metabolic disease after diabetes and poses a serious threat to the lives and health of the Chinese people [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Therefore, the development of safe and effective methods for HUA prevention and control is urgently needed.\u003c/p\u003e \u003cp\u003eThis study constructed an HUA mouse model by administering potassium oxonate and hypoxanthine via gavage, which increased the intake of high-purine foods and reduced uric acid excretion. The results revealed that the levels of UA, Cr, and BUN in the serum of the model mice were significantly increased, and severe damage was observed in both renal and glomerular tissues, which is consistent with the symptoms of HUA [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. These results indicate that the HUA model in this study was successful. After the oral administration of the DZ water extract to HUA mice, the levels of UA, Cr, and BUN in the serum of HUA mice were significantly reduced, and the degree of damage to kidney and glomerular tissues was significantly reduced. These findings indicate that DZ can be used to treat HUA in mice and preliminarily suggest that DZ may have therapeutic effects on HUA. To further evaluate the anti-HUA effect of DZ, this study selected 30 HUA patients as experimental subjects. We observed that after drinking 10 g of DZ daily for 1 week, the serum UA levels of the HUA volunteers decreased. After drinking DZ daily for 4 weeks, the UA levels of most HUA volunteers decreased to within the normal range. These results once again indicate that DZ has the ability to prevent and treat HUA.\u003c/p\u003e \u003cp\u003eMetabolomics is a research method that imitates the research ideas of genomics and proteomics, quantitatively analyses all metabolites in an organism, and searches for the relative relationships among metabolites and physiological and pathological changes. It is an integral part of systems biology [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Metabolomics can be used to study drug therapy for diseases at the overall metabolic level and has been widely used to investigate the pharmacological mechanisms of plants [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This study conducted serum metabolomics analysis on various groups of mice and revealed that DZ can reverse the disorders of pyrimidine metabolism, histidine metabolism, and riboflavin metabolism caused by HUA. Pyridine metabolism, histidine metabolism, and riboflavin metabolism are involved in purine metabolism and play important roles in the pathogenesis of HUA. These findings suggest that DZ may treat HUA by improving pyrimidine metabolism, histidine metabolism, and riboflavin metabolism.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThrough in-depth research on \u003cem\u003eEucommia folium\u003c/em\u003e, it has been confirmed that it is nontoxic and very safe. In China, \u003cem\u003eEucommia folium\u003c/em\u003e is also recognized as a medicinal and edible plant that can be directly consumed as food [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. This study used \u003cem\u003eEucommia folium\u003c/em\u003e as a single raw material and used a series of conventional physical methods to prepare a tea (DZ). The results of this study revealed that DZ significantly reduced the serum UA levels in HUA mice, and after HUA volunteers drank DZ, their serum UA contents decreased. These results suggest that DZ may have therapeutic effects on HUA. Therefore, it may be more suitable for the prevention and treatment of HUA, especially for the prevention of HUA.\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThere are several limitations to this study. ① DZ water extract is a mixture, and the active ingredients for anti-HUA effects are not yet clear. ② This study lacked research on the mechanism of the anti-HUA effect of DZ. This study revealed decreased UA levels in HUA volunteers after they drank DZ, lacked a blank control group, and cannot directly prove that DZ has anti-HUA effects. Our team will gradually address these issues in future research.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQing Hao and Ying Liu contributed equally to this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJichun Han: Conceptualisation, Methodology, Data curation, Validation, Formal analysis, Investigation, Resources, Visualisation, Writing \u0026ndash; original draft; Qing Hao, Ying Liu, Zikun Zhai, Bo Wang, Lin Jiang, and Qiusheng Zheng: Conceptualisation, Methodology, Validation, Formal analysis, Investigation, Resources, Visualisation, Writing \u0026ndash; original draft; Jichun Han, Xiangcheng Fan, Jiawei Su, Maiting Zhang, and Jiajun Li: Conceptualisation, Validation, Writing \u0026ndash; review and editing; Shuo Chen, Ziyun Ye, Qiusheng Zheng, and Xiangcheng Fan: Conceptualisation, Validation, Writing \u0026ndash; review and editing, Supervision; JCH and Xiangcheng Fan: Investigation, Resources.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding authors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to Jichun Han or Xiangcheng Fan.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary Information\u003c/strong\u003e The online version contains supplementary material available at\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e Not Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e Not Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e Not Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest/Competing Interests\u003c/strong\u003e The authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Number\u003c/strong\u003e Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHuang Q, Tan JB, Zeng XC et al (2021) Lignans and phenolic constituents from Eucommia ulmoides Oliver. 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Heliyon 10:e24851. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.heliyon.2024.e24851\u003c/span\u003e\u003cspan address=\"10.1016/j.heliyon.2024.e24851\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"plant-foods-for-human-nutrition","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Plant Foods for Human Nutrition](https://www.springer.com/journal/11130)","snPcode":"11130","submissionUrl":"https://submission.nature.com/new-submission/11130/3","title":"Plant Foods for Human Nutrition","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Eucommia folium, Hyperuricaemia, Homology-of-medicine-and-food, Functional food","lastPublishedDoi":"10.21203/rs.3.rs-5233926/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5233926/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe aim of this study was to investigate the antihyperuricaemic (HUA) effect of \u003cem\u003eEucommia folium\u003c/em\u003e after preparing a tea made from its leaves (abbreviated as DZ) which has the ability to prevent and treat HUA. In this study, a mouse HUA model was established via gavage of potassium oxonate and hypoxanthine, and this HUA model was treated with DZ to investigate the therapeutic effect of DZ on HUA. This study recruited 30 HUA volunteers, who drank 10 g of DZ daily for 4 consecutive weeks. The serum HUA levels of UA volunteers were measured once per week to observe the anti-HUA efficacy of DZ at the clinical level. Animal experiments have shown that DZ has therapeutic effects on HUA. DZ effectively reduces the levels of uric acid (UA), creatinine (Cr), and urea nitrogen (BUN) in the serum of HUA mice; decreases xanthine oxidase (XOD) activity in the serum; and alleviates damage to kidney tissues and glomeruli. Metabolomic analysis revealed that DZ affects multiple metabolites, such as orotidine, orotic acid, ureidosuccinic acid, 1-methylhistidine, and other metabolites, and these metabolites are involved mainly in pyrimidine metabolism, histidine metabolism, and riboflavin metabolism. Clinical research revealed that, after DZ was consumed, the UA levels in the HUA volunteers significantly decreased. DZ can prevent and treat HUA, and is in the same class of traditional Chinese medicines used in medicine and food, with extremely low toxicity and high safety. Therefore, DZ is suitable as a functional food for the prevention and treatment of HUA.\u003c/p\u003e","manuscriptTitle":"Eucommia folium can be prepared into tea with the ability to prevent and treat hyperuricemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-02 18:12:35","doi":"10.21203/rs.3.rs-5233926/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-12T06:41:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-10T19:19:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-09T23:24:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"Plant Foods for Human Nutrition","date":"2024-10-09T15:46:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"plant-foods-for-human-nutrition","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Plant Foods for Human Nutrition](https://www.springer.com/journal/11130)","snPcode":"11130","submissionUrl":"https://submission.nature.com/new-submission/11130/3","title":"Plant Foods for Human Nutrition","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"fc156d2d-60f6-45cd-98ad-c6fc47f7efae","owner":[],"postedDate":"November 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-02-23T08:23:30+00:00","versionOfRecord":[],"versionCreatedAt":"2024-11-02 18:12:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5233926","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5233926","identity":"rs-5233926","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}