Astragalus membranaceus ultrafine powder alleviates hyperuricemia by regulating the gut microbiome and reversing bile acid and adrenal hormone biosynthesis dysregulation

Ethnopharmacological relevanceMetabolic syndrome is closely related to the intestinal microbiota and disturbances in the host metabolome. Hyperuricemia (HUA), a manifestation of metabolic syndrome, can induce various cardiovascular diseases and gout, seriously affecting a patient’s quality of life. Astragalus membranaceus has a long history as a commonly used traditional Chinese medicine to treat kidney disease in China and East Asia.Materials and methodsWe compared the therapeutic effect of benzbromarone and two different doses Astragalus membranaceus ultrafine powder (AMUP) in rats with HUA. Ultra-performance liquid chromatography-mass spectrometer was used to analyze the AMUP metabolism in the plasma, urine, and feces. Further, 16S ribosome RNA sequencing and feces metabolomic were performed to capture the variation of the gut microbiota and metabolites changes before and after drug administration.ResultsAMUP had a notable impact on reducing blood uric acid levels while protecting the liver and kidney. Drug metabolism analysis demonstrated that effective constituent flavonoids are distributed in the blood, whereas saponins remain in the intestine. Gut microbiota analysis showed that low-dose AMUP ameliorated HUA-induced gut dysbiosis by reducing the abundance of harmful bacteria and increasing that of some beneficial bacteria with anti-inflammatory properties, such as Clostridia, Lachnospiraceae, and Muribaculaceae. In addition, HUA-induced changes in metabolite contents in bile acid and adrenal hormone biosynthesis pathways were restored after treatment with AMUP.ConclusionLow-dose AMUP exerts remarkable therapeutic effects on HUA by regulating the gut microbiome and mediating gut metabolism pathways associated with uric acid excretion.     

Unraveling the mystery of efficacy in Chinese medicine formula: New approaches and technologies for research on pharmacodynamic substances

Traditional Chinese medicine (TCM) is the key to unlock treasures of Chinese civilization. TCM and its compound play a beneficial role in medical activities to cure diseases, especially in major public health events such as novel coronavirus epidemics across the globe. The chemical composition in Chinese medicine formula is complex and diverse, but their effective substances resemble “mystery boxes”. Revealing their active ingredients and their mechanisms of action has become focal point and difficulty of research for herbalists. Although the existing research methods are numerous and constantly updated iteratively, there is remain a lack of prospective reviews. Hence, this paper provides a comprehensive account of existing new approaches and technologies based on previous studies with an in vitro to in vivo perspective. In addition, the bottlenecks of studies on Chinese medicine formula effective substances are also revealed. Especially, we look ahead to new perspectives, technologies and applications for its future development. This work reviews based on new perspectives to open horizons for the future research. Consequently, herbal compounding pharmaceutical substances study should carry on the essence of TCM while pursuing innovations in the field.     

Metabonomics study of the effects of traditional Chinese medicine formula Ermiaowan on hyperuricemic rats

To explore the global mechanism of Ermiaowan on hyperuricemia regulation, the holistic function of Ermiaowan for hyperuricemia in rats was firstly assessed by the urinary metabonomics method which was based on ultra‐high performance liquid chromatography with electrospray ionization quadrupole time‐of‐flight mass spectrometry. The urinary targeted metabonomics approach combined with the serum biochemical analysis and histological assay was conducted to verify the research result. As a result, the significant differences in metabolic profiles were observed from Ermiaowan‐treated group, model group, and healthy control group by using multivariate statistical approaches. Twenty therapeutic related metabolites were identified in response to the therapeutic effects of Ermiaowan, which were mainly associated with purine metabolism, pyrimidine metabolism, tryptophan metabolism, tricarboxylic acid cycle, and tyrosine metabolism. In addition, the urinary targeted metabonomics study showed that Ermiaowan can better restore the disturbed pathways than Phellodendri cortex and Atractylodis rhizome. The biochemical assay and histopathological assay confirmed that Ermiaowan could significantly reduce uric acid and fibrosis areas of kidney. These results provided new insights into the mechanism of Ermiaowan on hyperuricemia.     

Metabolomic profiles delineate the effect of Sanmiao wan on hyperuricemia in rats

A serum metabolomic method based on ultra‐high‐performance liquid chromatography coupled with mass spectrometry was developed to characterize hyperuricemia‐related metabolic profiles and delineate the mechanism of Sanmiao wan (SMW), a traditional Chinese medicine (TCM), in treating hyperuricemic rats. With partial least‐squares discriminant analysis for classification and selection of biomarkers, 13 potential biomarkers in mouse serum were identified in the screen, primarily involved in purine metabolism, arginine and proline metabolism, citrate cycle, phenylalanine metabolism, tryptophan metabolism and glycerophospholipid metabolism. Taking these potential biomarkers as screening indexes, SMW could reverse the pathological process of hyperuricemia through partially regulating the perturbed metabolic pathway except for glycerophospholipid metabolism. Our results showed that a metabolomic approach offers a useful tool to identify hyperuricemia‐related biomarkers and provides a new methodological cue for systematically dissecting the underlying efficacies and mechanisms of TCM in treating hyperuricemia.     

Natural Xanthine Oxidase Inhibitor 5-O-Caffeoylshikimic Acid Ameliorates Kidney Injury Caused by Hyperuricemia in Mice

Xanthine oxidase (XOD) inhibition has long been considered an effective anti-hyperuricemia strategy. To identify effective natural XOD inhibitors with little side effects, we performed a XOD inhibitory assay-coupled isolation of compounds from Smilacis Glabrae Rhizoma (SGR), a traditional Chinese medicine frequently prescribed as anti-hyperuricemia agent for centuries. Through the in vitro XOD inhibitory assay, we obtained a novel XOD inhibitor, 5-O-caffeoylshikimic acid (#1, 5OCSA) with IC₅₀ of 13.96 μM, as well as two known XOD inhibitors, quercetin (#3) and astilbin (#6). Meanwhile, we performed in silico molecular docking and found 5OCSA could interact with the active sites of XOD (PDB ID: 3NVY) with a binding energy of −8.6 kcal/mol, suggesting 5OCSA inhibits XOD by binding with its active site. To evaluate the in vivo effects on XOD, we generated a hyperuricemia mice model by intraperitoneal injection of potassium oxonate (300 mg/kg) and oral gavage of hypoxanthine (500 mg/kg) for 7 days. 5OCSA could inhibit both hepatic and serum XOD in vivo, together with an improvement of histological and multiple serological parameters in kidney injury and HUA. Collectively, our results suggested that 5OCSA may be developed into a safe and effective XOD inhibitor based on in vitro, in silico and in vivo evidence.     

Comparative pharmacokinetic study of the main components of cortex fraxini after oral administration in normal and hyperuricemic rats

Cortex Fraxini is an important traditional Chinese herbal medicine used for the treatment of gout and hyperuricemia. An efficient and rapid ultra‐performance liquid chromatography mass spectrometry method was developed and validated for simultaneous quantitation of six coumarins (aesculin, fraxin, aesculetin, fraxetin, sopoletin and 7‐hydroxycoumarin) in normal and hyperuricemic rats plasma after oral administration of Cortex Fraxini. The method could successfully be applied for pharmacokinetics studies. The pharmacokinetic behavior of six coumarins in normal and hyperuricemia rats plasma was determined. Results showed that, for some of analytes, the pharmacokinetic parameters (AUC_0–t , AUC_0–∞, C _max, T _max and CL ) were significantly different between normal and hyperuricemic rats. The different pharmacokinetic parameters might result from renal impairment or a change of metabolic enzymes in the pathological state. The pharmacokinetic study in pathological state could provide more useful information to guide the clinical use of traditional Chinese herbal medicine.     

常见蔬菜醇提物对黄嘌呤氧化酶的抑制作用

体内尿酸浓度过高将导致高尿酸血症,会引起痛风的发作。黄嘌呤氧化酶既能催化次黄嘌呤生成黄嘌呤,又能催化黄嘌呤生成尿酸。为了提供健康的饮食依据,减少或预防痛风疾病的发生,文中研究了40种常见蔬菜的乙醇提取物对黄嘌呤氧化酶活性的体外抑制作用,结果表明在500mg·L-1用量下,24种蔬菜醇提物对黄嘌呤氧化酶有不同程度抑制作用;醇提物抑制效果最好的4种蔬菜分别是藜蒿、香菜、荷兰豆、红辣椒,抑制率依次为(65.7±0.26)%、(44.2±0.1)%、(40.1±0.12)%、(36.6±0.35)%。体内动物实验表明此4种醇提物在由氧嗪酸钾引起的高尿酸血症模型小鼠体内均具有较强降尿酸作用,并能抑制肝脏黄嘌呤氧化酶的活性,其中藜蒿醇提物效果最显著。     

Biopharmaceutical Study on Nobiletin-Loaded Amorphous Solid Dispersion with Improved Hypouricemic Effect

The present study aimed to develop an amorphous solid dispersion of nobiletin (ASD/NOB) using hydroxypropyl cellulose-SSL (HPC-SSL) to improve the pharmacokinetic properties and hypouricemic effect of NOB. ASD/NOB was prepared by the freeze-drying method (ASD/NOB). ASD/NOB was characterized with a focus on crystallinity, dissolution, pharmacokinetic behavior, and hypouricemic action in a rat model of hyperuricemia. ASD/NOB showed significant improvement in dissolution behavior, as evidenced by a 4.4-fold higher dissolved NOB concentration than crystalline NOB at 2 h in distilled water. After the oral administration of ASD/NOB (50 mg NOB/kg) in rats, higher systemic exposure to NOB was observed with an 18-fold enhancement in oral bioavailability, and the T_max value of orally administered ASD/NOB was 60% shorter than that of orally administered crystalline NOB. In a rat model of hyperuricemia, orally dosed ASD/NOB showed an improved hypouricemic effect by a 16% reduction in the plasma uric acid level compared with orally administered crystalline NOB. Based on these findings, ASD/NOB may be an efficacious dosage option to improve the nutraceutical potential of NOB for the treatment of hyperuricemia.     

Towards the Use of Adsorption Methods for the Removal of Purines from Beer

Beer corresponds to a fermented alcoholic beverage composed of several components, including purine compounds. These molecules, when ingested by humans, can be catabolized into uric acid, contributing to uric acid’s level increase in serum, which may lead to hyperuricemia and gout. To assure a proper management of this disease, physicians recommend restrictive dietary measures, particularly by avoiding the consumption of beer. Therefore, it is of relevance to develop efficient methods to remove purine compounds from alcoholic beverages such as beer. In this review, we provide an introduction on fermented alcoholic beverages, with emphasis on beer, as well as its purine compounds and their role in uric acid metabolism in the human body in relation to hyperuricemia and gout development. The several reported enzymatic, biological and adsorption methods envisaging purine compounds’ removal are then reviewed. Some enzymatic and biological methods present drawbacks, which can be overcome by adsorption methods. Within adsorption methods, adsorbent materials, such as activated carbon or charcoal, have been reported and applied to beer or wort samples, showing an excellent capacity for adsorbing and removing purine compounds. Although the main topic of this review is on the removal of purine compounds from beer, other studies involving other matrices rather than beer or wort that are rich in purines are included, since they provide relevant clues on designing efficient removal processes. By ensuring the selective removal of purine compounds from this beverage, beer can be taken by hyperuricemic and gouty patients, avoiding restrictive dietary measures, while decreasing the related healthcare economic burden.     

Determination of purine contents of alcoholic beverages using high performance liquid chromatography

The purine contents of alcoholic beverages were determined in order to utilize them in the dietary care of gout and hyperuricemia. In the management of these diseases, restriction of both alcohol and purine intake are important. The method employed in this study is a quantitative determination of purine contents by HPLC. Alcoholic beverages were hydrolyzed to corresponding purine bases, which were then separated by HPLC, and base peaks were identified using an enzymatic peak‐shift technique. This method is sufficiently accurate and reproducible to examine the purine contents of various alcoholic beverages that patients consume. Purine contents were as follows: spirits, 0.7–26.4 µmol/L; regular beer, 225.0–580.2 µmol/L; low‐malt beer, 193.4–267.9 µmol/L; low‐malt and low‐purine beer, 13.3 µmol/L; other liquors, 13.1–818.3 µmol/L. Some local and low‐alcohol beers were found to contain about 2.5 times more purines than regular beer. As some alcoholic beverages contain considerable amounts of purines, we recommend that excess consumption of these beverages be avoided. These data should be useful in the management of hyperuricemia and gout, not only for patients but also for physicians. Copyright © 2009 John Wiley & Sons, Ltd.