Frontiers in Pharmacology
·
2022
·
IF 5.988
Gao Tianshu,Xu Jin,Xiao Yuxiao,Li Jiaqi,Hu Weifeng,Su Xiaoyu,Shen Xudong,Yu Wan,Chen Zhen,Huang Baosheng,Li Honglei,Wang Xing
Objective: To observe the antioxidative effects of N-(9,10-anthraquinone-2-ylcarbonyl) xanthine oxidase inhibitors (NAY) in vitro and in vivo models of hyperuricemia and explore the mechanism.Methods: A classical experimental method of acute toxicity and a chronic toxicity test were used to compare the toxic effects of different doses of NAY in mice. The hyperuricemia mouse model was established by gavage of potassium oxonate in vivo. After treatment with different doses of NAY (low dose: 10 mg/kg, medium dose: 20 mg/kg, and high dose: 40 mg/kg) and allopurinol (positive drug, 10 mg/kg), observe the levels of uric acid (UA), creatinine (CRE), and urea nitrogen (BUN) in urine and serum, respectively, and detect the activities of xanthine oxidase in the liver. The hyperuricemia cell model was induced by adenosine and xanthine oxidase in vitro. The cells were given different doses of NAY (50, 100, and 200 μmol/L) and allopurinol (100 μmol/L). Then the culture supernatant UA level of the medium was measured. The next step was to detect the xanthine oxidase activity in the liver and AML12 cells, and the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammatory factors in the kidney and serum of mice. Western blot was used to detect xanthine oxidase protein expression in mouse liver tissue and AML12 cells, ASC, Caspase-1, NLRP3, GLUT9, OAT1, and OAT3 protein expression in mouse kidney tissue and HK-2 cells. Hematoxylin–eosin staining was used to stain the liver and kidney tissues of mice and observe the tissue lesions.Results: NAY had little effect on blood routine and biochemical indexes of mice, but significantly reduced the serum UA level. NAY significantly reduced the level of UA in hyperuricemia mice and cells by inhibiting xanthine oxidase activity and reduced the levels of TNF-α, IL-6, and other inflammatory factors in serum and kidney of mice. NAY can inhibit inflammation by inhibiting the NLRP3 pathway. In addition, NAY can downregulate GLUT9 protein expression and upregulate OAT1 and OAT3 protein expression to reduce the UA level by promoting UA excretion and inhibiting UA reabsorption.Conclusion: These findings suggested that NAY produced dual hypouricemic actions. On the one hand, it can inhibit the formation of UA by inhibiting xanthine oxidase inhibitors activity, and on the other hand, it can promote the excretion of UA by regulating the UA transporter. It provides new ideas for the development of hyperuricemia drugs in the future.
研究领域:
药理学
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生物化学
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分子生物学
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炎症研究
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DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2021
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IF 7.963
Xinying Wang,Ming Gao,Zihan Wang,Weiqi Cui,Jingxian Zhang,Weijie Zhang,Yu Xia,Bo Wei,Youcai Tang,Xia Xu
Bisphenol A (BPA) is widely used to manufacture packaging materials for various daily necessities and causes harmful effects in organs, especially liver injury, by generating oxidative stress. Oridonin, an active diterpenoid isolated from Rabdosia rubescens (Hemsl.) Hara , has been reported to possess a wide range of pharmacological activities including anti-inflammatory, antioxidative and antiapoptotic effects. However, the role of oridonin in BPA--induced liver injury and its potential protective mechanism have not been well characterized. In this research, we explored the metabolic alterations in the liver tissue of rats after exposure to BPA with or without pretreatment with oridonin for 14 days by metabolomics analysis based on UPLC-MS/MS. Rats were randomly divided into groups as follows: Control, Vehicle, Oridonin (10 mg/kg), Bisphenol A (500 mg/kg), bisphenol A + Oridonin (500 + 10 mg/kg), Bisphenol A + Diammonium glycyrrhizinate (500 + 40 mg/kg). The biochemical results showed that oridonin significantly reduced the levels of AST and ALT ( P < 0.05), ameliorated the abnormal histopathological changes and reduced hepatic apoptosis compared with the BPA group. Furthermore, metabolomics results revealed that purine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis and phenylalanine metabolism were reprogrammed, based on 28 identified significant differential metabolites among the Vehicle, BPA and BPA + oridonin groups. In-depth studies demonstrated that pretreatment with oridonin may play a protective role by restoring BPA-induced changes in oxidative stress and the activity of oxidase (XOD) ( P < 0.05). Additionally, oridonin could inhibit the activity of XOD by binding to it, therefore decreasing the reactive oxygen species (ROS) level, upregulating the content of hypoxanthine and xanthine, and reducing the level of uric acid in the liver ( P < 0.05). This research presents the potential protective mechanisms of oridonin on BPA-induced liver injury at the metabolic level, which might be used to identify new protective agents that prevent BPA-induced liver injury.
研究领域:
药理学
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毒理学
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代谢生物学
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DOI
PubMed
高影响因子
INDUSTRIAL CROPS AND PRODUCTS
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2018
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IF 3.849
Yizhen Li,Yin Wan,Ruyi Li,Laojiu Xu,Mingyong Xie,Guiming Fu
In this study, the caffeoylquinic acid (CQA) extract solution of the Artemisia selengensis Turcz (AST) leaves prepared by 70% ethanol reflux method was separated with petroleum ether, ethyl acetate, and water-saturated n -butanol to obtain the proper solvent to purify CQAs. Results showed that the ethyl acetate fraction (EAF) exhibited the highest total chlorogenic acid content (TCC) (241.46 ± 0.00 mg/g dry fraction), followed by the water-saturated n -butanol fraction ( n BuF) (TCC = 62.30 ± 0.82 mg/g dry fraction). Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry and high-performance liquid chromatography photodiode array were used to qualitatively and quantitatively determine the CQAs in these two fractions. In EAF, four CQAs, namely, 3-CQA, 3,5-diCQA, 3,4-diCQA, and 4,5-diCQA, were identified with the contents of 5.69 ± 0.03, 106.65 ± 0.83, 15.65 ± 0.24, and 28.08 ± 0.82 mg/g, respectively. Six CQAs, namely, 3-CQA, 4-CQA, 1,3-diCQA, 3,5-diCQA, 3,4-diCQA, and 4,5-diCQA, with contents of 16.57 ± 0.23, 3.22 ± 0.55, 4.49 ± 0.01, 16.86 ± 0.24, 7.35 ± 0.11, and 6.41 ± 0.13 mg/g, respectively, were identified in n BuF. Quantitative analysis of the six CQAs in AST leaves have not been reported, and 1,3-diCQA has been found in AST leaves for the first time. Moreover, either EAF or n BuF and the six CQA reference compounds showed certain inhibitory activity on xanthine oxidase (XOD) in vitro . EAF demonstrated a stronger XOD inhibitory effect (IC 50 = 1.67 mg/mL) than n BuF. Among the six CQA compounds, 3,4-diCQA had the lowest IC 50 of 12.80 μM, whereas 1,3-diCQA and 3-CQA had IC 50 values of 23.69 and 28.29 μM, respectively. The inhibitory activity of 4-CQA was weak. These findings indicated that CQAs are the major components inhibiting the XOD activity in vitro in AST leaves.
研究领域:
植物化学
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药理学
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产品关联
DOI
高影响因子
JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS
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2020
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IF 2.252
Xiao-Yun Xiong,Jun Liang,Sheng-Ya Guo,Ming-Zhu Dai,Jia-Li Zhou,Yong Zhang,Yi Liu
Introduction: This study was aimed to assess uric acid (UA)-lowering effect and its possible mechanisms of a natural complex product Yaocha in a live zebrafish model. Methods: The zebrafish high UA model was established by feeding 5 dpf zebrafish with both an uricase inhibitor potassium oxonate at 10 mM and an UA synthesis precursor xanthine sodium at 0.5 mM for 24 h. Yaocha was administered to the high UA zebrafish through soaking at 3 various concentrations, with allopurinol as a positive control. UA level, xanthine oxidase (XOD) activity, and mRNA expression of hypoxanthine guanine-phosphoribosyltransferases transferase (HPRT1) and organic anion transporter 1 (OAT1) were measured. Results: Yaocha effectively reduced UA level and inhibited xanthine oxidase (XO) activity in the high UA zebrafish. Yaocha could be a potential therapeutics for hyperuricemia through up-regulating HPRT1 and OAT1 gene expression and suppressing XO activity. Discussion: These results suggested that Yaocha hold a potential for high UA prevention and therapy, possibly through inhibiting UA production and promoting urate secretion and purine conversion.
研究领域:
医学
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生物化学
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产品关联
DOI
PubMed
高影响因子
Foods
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2023
·Vol. 12
·期 5
·982
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IF 5.2
Xiaoling Chen,Weiliang Guan,Yujin Li,Jinjie Zhang,Luyun Cai
Hyperuricemia is linked to a variety of disorders that can have serious consequences for human health. Peptides that inhibit xanthine oxidase (XO) are expected to be a safe and effective functional ingredient for the treatment or relief of hyperuricemia. The goal of this study was to discover whether papain small yellow croaker hydrolysates (SYCHs) have potent xanthine oxidase inhibitory (XOI) activity. The results showed that compared to the XOI activity of SYCHs (IC50= 33.40 ± 0.26 mg/mL), peptides with a molecular weight (MW) of less than 3 kDa (UF-3) after ultrafiltration (UF) had stronger XOI activity, which was reduced to IC50= 25.87 ± 0.16 mg/mL (p< 0.05). Two peptides were identified from UF-3 using nano-high-performance liquid chromatography–tandem mass spectrometry. These two peptides were chemically synthesized and tested for XOI activity in vitro. Trp-Asp-Asp-Met-Glu-Lys-Ile-Trp (WDDMEKIW) (p< 0.05) had the stronger XOI activity (IC50= 3.16 ± 0.03 mM). The XOI activity IC50of the other peptide, Ala-Pro-Pro-Glu-Arg-Lys-Tyr-Ser-Val-Trp (APPERKYSVW), was 5.86 ± 0.02 mM. According to amino acid sequence results, the peptides contained at least 50% hydrophobic amino acids, which might be responsible for reducing xanthine oxidase (XO) catalytic activity. Furthermore, the inhibition of the peptides (WDDMEKIW and APPERKYSVW) against XO may depend on their binding to the XO active site. According to molecular docking, certain peptides made from small yellow croaker proteins were able to bind to the XO active site through hydrogen bonds and hydrophobic interactions. The results of this work illuminate SYCHs as a promising functional candidate for the prevention of hyperuricemia.Keywords:xanthine oxidase inhibitor;peptides;small yellow croaker;identification;molecular docking
研究领域:
生物化学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PROCESS BIOCHEMISTRY
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2020
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IF 2.952
Jianmin Chen,Qinglian Li,Yaling Ye,Mengnan Ran,Zhipeng Ruan,Nan Jin
Xanthine oxidase (XO) catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid. Excessive production of uric acid leads to hyperuricaemia. Due to the serious side effects of allopurinol, it is an urgent need to explore new XO inhibitors. Herein, the effects of theaflavin (TF1) on XO and anti-hyperuricaemia effect in hyperuricemic mice were investigated. Kinetic analysis indicate that TF1 is a reversible competitive inhibitor and has a significant inhibitory effect on XO with an IC 50 value of 63.17 ± 0.13 μmol/L. Analysis of fluorescence spectra suggests that TF1 causes the obvious fluorescence quenching of XO, which is mainly driven by hydrophobic interactions and hydrogen bonds. Docking studies demonstrate that TF1 interacts with dozens of amino acid residues surrounded in the active cavity of XO, including Glu-879, Pro-1012, Thr-1010, Val-1011, Lys-771, Glu-802, Pro-1076, Leu-873, Leu-1014, Asn-768, Leu-648 and Phe-649. The inhibitory mechanism may be the insertion of TF1 into the active site of XO, which hinders the substrate xanthine to enter into the site. Furthermore, the results from animal experiments demonstrate that TF1 is effective in reducing serum uric acid in mice. These findings suggest that TF1 may be a potential drug candidate for the treatment of hyperuricaemia.
研究领域:
药理学
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生物化学
✓ 已验证
DOI
高影响因子
PHYTOMEDICINE
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2020
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IF 4.268
Yanyu Chen,Zean Zhao,Yongmei Li,Yang Yang,Lu Li,Yu Jiang,Cuiting Lin,Ying Cao,Pingzheng Zhou,Yuanxin Tian,Ting Wu,Jianxin Pang
Background Insufficient renal urate excretion and/or overproduction of uric acid (UA) are the dominant causes of hyperuricemia . Baicalein (BAL) is widely distributed in dietary plants and has extensive biological activities , including antioxidative, anti-inflammatory and antihypertensive activities. Purpose: To investigate the anti-hyperuricemic effects of BAL and the underlying mechanisms in vitro and in vivo . Methods We investigated the inhibitory effects of BAL on GLUT9 and URAT1 in vitro through electrophysiological experiments and 14 C-urate uptake assays . To evaluate the impact of BAL on serum and urine UA, the expression of GLUT9 and URAT1, and the activity of xanthine oxidase (XOD), we developed a mouse hyperuricemia model by potassium oxonate (PO) injection. Molecular docking analysis based on homology modeling was performed to explain the predominant efficacy of BAL compared with the other test compounds. Results BAL dose-dependently inhibited GLUT9 and URAT1 in a noncompetitive manner with IC 50 values of 30.17 ± 8.68 μM and 31.56 ± 1.37 μM, respectively. BAL (200 mg/kg) significantly decreased serum UA and enhanced renal urate excretion in PO-induced hyperuricemic mice. Moreover, the expression of GLUT9 and URAT1 in the kidney was downregulated, and XOD activity in the serum and liver was suppressed. The docking analysis revealed that BAL potently interacted with Trp336, Asp462, Tyr71 and Gln328 of GLUT9 and Ser35 and Phe241 of URAT1. Conclusion These results indicated that BAL exerts potent antihyperuricemic efects through renal UA excretal promotion and serum UA production. Thus, we propose that BAL may be a promising treatment for the prevention of hyperuricemia owing to its multitargeted inhibitory activity.
研究领域:
药理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2023
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IF 5.1
Jiling Song,Zhanwei Wang,Yu Chi,Yong Zhang,Chenyi Fang,Yuting Shu,Jing Cui,Helong Bai,Jing Wang
Xanthine oxidase (XO) plays a critical role in the progression of gout. We showed in a previous study that Sanghuangporus vaninii ( S. vaninii ), a perennial, medicinal, and edible fungus traditionally used to treat various symptoms, contains XO inhibitors. In the current study, we isolated an active component of S. vaninii using high performance countercurrent chromatography and identified it as davallialactone using mass spectrometry with 97.726 % purity. A microplate reader showed that davallialactone had mixed inhibition of XO activity with a half-inhibitory concentration value of 90.07 ± 2.12 μM. In addition, the collision between davallialactone and XO led to fluorescence quenching and conformational changes in XO, which were mainly driven by hydrophobicity and hydrogen bonding. Molecular simulations further showed that davallialactone was located at the center of the molybdopterin (Mo-Pt) of XO and interacted with amino acid residues Phe798, Arg912, Met1038, Ala1078, Ala1079, Gln1194, and Gly1260, suggesting that entering the enzyme-catalyzed reaction was unfavorable for the substrate. We also observed face-to-face π-π interactions between the aryl ring of davallialactone and Phe914. Cell biology experiments indicated that davallialactone reduced the expression of the inflammatory factors, tumor necrosis factor alpha and interleukin-1 beta ( P < 0.05), can effectively alleviate cellular oxidative stress. This study showed that davallialactone significantly inhibits XO and has the potential to be developed into a novel medicine to prevent hyperuricemia and treat gout.
研究领域:
药理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2025
·
IF 5.9
Jiaqi Wen,Yijing Liao,Deming Gong,Guowen Zhang
Inhibition of xanthine oxidase (XO) activity is an effective strategy for the treatment of hyperuricemia and gout. However, some nutrients (such as lipids, proteins, and vitamins, etc) in the daily diet may affect the binding of enzyme inhibitors to XO. The effects of three unsaturated fatty acids (USFAs, namely oleic acid, linoleic acid and α-linolenic acid) on the inhibition of XO by phloretin were investigated in the study. The results showed that USFAs significantly enhanced the inhibitory effect of phloretin on XO, primarily due to the changes in secondary structure and increased binding affinity. The order of enhancement was α-linolenic acid > oleic acid > linoleic acid. The USFAs synergistically destroyed the hydrogen bond network structure of XO with phloretin, resulting in a looser and more disordered XO structure. Moreover, phloretin formed more hydrogen bonds, hydrophobic interactions and van der Waals forces with the amino acid residues of XO in the presence of USFAs, which eventually increased the inhibitory ability of phloretin on XO. The study may provide a new perspective for the dietary nutrition intervention of the patients with hyperuricemia and gout.
研究领域:
营养学
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生物化学
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药理学
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产品关联
DOI
高影响因子
Journal of Functional Foods
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2024
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IF 3.8
Zhizhou Li,Hui Wang,Shiwei Sun,Zhongbai Shao,Chaoyi Lv,Xiaoyue Dong,Lu Wang,Wei Wang
In the course of our research on utilizing edible flower resources to promote health, five ellagitannins ( 1 – 5 ) were isolated from pomegranate ( Punica granatum L.) flower by bioassay-guided fractionation. Among them, mallotusinin ( 1 ) and tercatain ( 2 ) were first isolated from pomegranate flower, and punicatannin D ( 4 ) was an unprecedented compound. Compounds 1 – 3 exhibited significant xanthine oxidase (XO) inhibitory activity compared with allopurinol, and a potent inhibition on α -glucosidase that was superior to acarbose was observed for compounds 1 – 4 . The XO inhibitory activity is positively correlated with the amount of galloyl moiety ( 3 > 2 > 1 ). Presenting tetrahydroxydibenzofuranoyl substituent or increasing the number of galloyl group enhanced the inhibition capacity of α -glucosidase ( 1 > 3 > 2 ). The inhibitory mechanism was further clarified in terms of kinetic studies and molecular docking. This study revealed that the ellagitannins present in pomegranate flower might be promising functional food ingredients with anti-hyperuricemia and anti-hyperglycemia properties.
研究领域:
植物化学
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药理学
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功能性食品研究
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产品关联
DOI
高影响因子
BIOTECHNOLOGY AND APPLIED BIOCHEMISTRY
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2024
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IF 3.2
Jianmin Chen,Juan Chen,Baozhu Feng,Meilian Ning,Wanhui Wu,Shiqi Zou
Gout predominantly stems from hyperuricemia, precipitating the accumulation of urate crystals and consequent joint inflammation, swelling, and pain, thereby compromising the quality of life and presenting a formidable medical dilemma. Although conventional treatments like allopurinol and febuxostat target uric acid reduction via xanthine oxidase (XO) inhibition, they often entail adverse effects, prompting the exploration of safer alternatives. Resveratrol, a polyphenolic compound abundant in fruits and vegetables, has emerged as a potential XO inhibitor. However, its precise inhibitory mechanisms remain poorly understood. This study aims to comprehensively investigate resveratrol's XO inhibition through mechanistic insights, molecular docking simulations, animal model experiments, and biochemical analysis, contributing valuable insights to the development of novel therapeutics for hyperuricemia and gout.
研究领域:
药理学
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生物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2016
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IF 3.138
Yin Wan,Bin Zou,Hailong Zeng,Lunning Zhang,Ming Chen,Guiming Fu
In this study, we analyzed the inhibitory effect of verbascoside against xanthine oxidase (XOD) in vitro by using animal model and in vivo by direct inhibition assay. Results showed that verbascoside could reduce uric acid in rat serum and inhibit XOD activity in rat liver. The IC 50 value of restraining XOD activity was 81.11 mg mL −1 . Fluorescence chromatographic analysis and circular dichroism spectroscopy indicated that the secondary structures of XOD were changed after incubation with verbascoside. The docking simulation showed that verbascoside could enter into the active site of XOD and form hydrogen bonding with amino acid residues (such as Lys-1045, Arg-880, Arg-912, Glu-1261 and Gln-1194). The results suggested that verbascoside, which is a naturally occurring water-soluble antioxidant, could be a potential low-toxicity XOD inhibitor for hyperuricemia treatment.
研究领域:
药理学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）