Journal of Functional Foods
·
2019
·
IF 3.197
Yin Wan,Fen Wang,Bin Zou,Yuefeng Shen,Yizhen Li,Axi Zhang,Guiming Fu
The mechanism underlying the reduction in uric acid levels in hyperuricemia rats by caffeic acid was investigated in this study. Different doses of caffeic acid (25, 50, and 100 mg/kg) were administered to hyperuricemia rats induced by the intraperitoneal injection of potassium oxonate. In vivo study showed that caffeic acid can down-regulate the transcription levels of URAT1 and GLUT9 mRNA and up-regulate the transcription levels of OAT1, UAT, and ABCG2 mRNA. In vitro study indicated caffeic acid competitively binds with xanthine oxidase to inhibit its activity, and the IC 50 value was 53.45 µM. It was concluded that caffeic acid decreases serum uric acid levels in hyperuricemia rats by binding with xanthine oxidase and inhibiting its catalytic activity and by regulating the mRNA transcription of the renal uric acid transporters.
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
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6
Zean Zhao,Xinhua Chen,Jiajun Luo,Mengyu Chen,Jian Luo,Jianjun Chen,Zhonghuang Li,Shanhe Wan,Ting Wu,Jiajie Zhang,Jianxin Pang,Yuanxin Tian
Previously, we reported a novel natural scaffold compound, isobavachin (4′,7-dihydroxy-8-prenylflavanone), as a highly potent hURAT1 inhibitor with anti-hyperuricemia effect. However, the structure-activity relationship remains unknown and the poor pharmacokinetic (PK) parameters may limit further clinical use. Herein, a series of isobavachin derivatives were rationally designed and synthesized to explore the structure-activity relationship of isobavachin target hURAT1, and to improve their PK properties. Among them, compounds 15d, 15f, 15g, 27b and 27d showed promising hURAT1 inhibitory activities, which could comparable to that of isobavachin (IC 50 = 0.24 μM). In addition, 27b also inhibited another urate reabsorption transporter GLUT9 with an IC 50 of 4.47 μM. Compound 27b displayed greater urate-lowering activity in a hyperuricemia mouse model at a dose of 10 mg/kg compared to isobavachin and lesinurad. Overall, our results suggest that compound 27b represents a novel, safe hURAT1 and GLUT9 dual-target inhibitor with excellent drug availability and is worthy of further investigation as an anti-hyperuricemia agent.
研究领域:
药物化学
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药理学
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药物发现
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产品关联
DOI
PubMed
高影响因子
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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产品关联
DOI
PubMed
高影响因子
AMERICAN JOURNAL OF CHINESE MEDICINE
·
2018
·Vol. 46
·期 03
·585-599
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IF 3.12
Tianqiao Yong,Shaodan Chen,Yizhen Xie,Diling Chen,Jiyan Su,Ou Shuai,Huiping Hu,Dan Zuo,Danling Liang
Ethanol and water extracts of Armillaria mellea were prepared by directly soaking A. mellea in ethanol (AME) at 65 ∘ C, followed by decocting the remains in water (AMW) at 85 ∘ C. Significantly, AME and AMW at 30, 60 and 120 mg/kg exhibited excellent hypouricemic actions, causing remarkable declines from hyperuricemic control (351 μ mol/L, P < 0 . 0 1 ) to 136, 130 and 115 μ mol/L and 250, 188 and 152 μ mol/L in serum uric acid, correspondingly. In contrast to the evident renal toxicity of allopurinol, these preparations showed little impacts. Moreover, they showed some inhibitory effect on XOD (xanthine oxidase) activity. Compared with hyperuricemic control, protein expressions of OAT1 (organic anion transporter 1) were significantly elevated in AME- and AMW-treated mice. The levels of GLUT9 (glucose transporter 9) expression were significantly decreased by AMW. CNT2 (concentrative nucleoside transporter 2), a key target for purine absorption in gastrointestinal tract was involved in this study, and was verified for its innovative role. Both AME and AMW down-regulated CNT2 proteins in the gastrointestinal tract in hyperuricemic mice. As they exhibited considerable inhibitory effects on XOD, we selected XOD as the target for virtual screening by using molecular docking, and four compounds were hit with high ranks. From the analysis, we concluded that hydrogen bond, Pi–Pi and Pi-sigma interactions might play important roles for their orientations and locations in XOD inhibition.
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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医学
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产品关联
DOI
PubMed
高影响因子
Foods
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2025
·Vol. 14
·期 3
·524
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IF 5.1
Zexuan Xu,Miaoyu Gan,Weiliang Guan,Fang Tian,Yuxi Wang,Jinjie Zhang,Luyun Cai
Hyperuricemia arises from imbalanced uric acid metabolism, contributing to gout and related chronic diseases. When traditional drugs are used to treat hyperuricemia, side effects are inevitable, which promotes the exploration of new bioactive compounds. Protein hydrolysates and peptides are gradually showing potential in the treatment of hyperuricemia. This study investigated the uric acid inhibitory activity of peptides extracted fromTrachurus japonicususing in silico and in vitro methods. We employed in silico virtual enzymolysis and experimental validation to identify bioactive peptides fromTrachurus japonicusproteins. Four peptides (DF, AGF, QPSF, and AGDDAPR) were comprehensively screened by molecular docking and database analysis. After solid-phase synthesis, the inhibitory effects of these peptides on hyperuricemia were further verified in vitro and at the cellular level. The results showed that all four peptides have good hyperuricemia-inhibiting activities. Molecular docking and molecular dynamics revealed that peptides DF and AGDDAPR affect the production of uric acid by binding to the active sites of urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), and xanthine oxidase (XOD), while peptides QPSF and AGF mainly influence the XOD active site, confirming that it is feasible to rapidly screen hyperuricemia-inhibiting peptides by molecular docking.
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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食品科学
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产品关联
DOI
PubMed
高影响因子
Nutrients
·
2024
·Vol. 16
·期 20
·3549
·
IF 4.8
Yiming Zhang,Shengying Zhu,Yueming Gu,Yanjing Feng,Bo Gao
Background/Objectives: Hyperuricemia (HUA) is a common metabolic disease caused by purine metabolic disorders in the body.Portulaca oleraceaL. (PO) is an edible wild vegetable. Methods: In this study, the regulatory effect of PO on HUA and its potential mechanism were initially elucidated through network pharmacology and experimental validation. Results: The results showed that PO from Sichuan province was superior to the plant collected from other habitats in inhibiting xanthine oxidase (XOD) activity. Berberine and stachydrine were isolated and identified from PO for the first time by UPLC-Q-Exactive Orbitrap MS. The potential molecular targets and related signaling pathways were predicted by network pharmacology and molecular docking techniques. Molecular docking showed that berberine had strong docking activity with XOD, and the results of in vitro experiments verified this prediction. Through experimental analysis of HUA mice, we found that PO can reduce the production of uric acid (UA) in the organism by inhibiting XOD activity. On the other hand, PO can reduce the body ‘s reabsorption of urate and aid in its excretion out of the body by inhibiting the urate transporter proteins (GLUT9, URAT1) and promoting the high expression of urate excretory protein (ABCG2). The results of H/E staining showed that, compared with the positive drug (allopurinol and benzbromarone) group, there was no obvious renal injury in the middle- and high-dose groups of PO extract. Conclusions: In summary, our findings reveal the potential of wild plant PO as a functional food for the treatment of hyperuricemia.
研究领域:
药理学
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代谢疾病
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植物化学
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分子生物学
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实验验证
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioengineered
·
2021
·
IF 3.269
Xia Zhao,Jing Wang,Liying Tang,Pei Li,Jing Ru,Yuzhi Bai
The study was designed to explore the effects of Withaferin A (WFA) on hyperuricemia-induced kidney injury and its action mechanism. Potassium oxonate (PO) was employed to establish the hyperuricemic mouse model. The pathological changes of renal tissue were evaluated by hematoxylin-eosin and masson trichrome staining. The levels of creatinine, blood urea nitrogen (BUN), uric acid (UA) and xanthine oxidase (XOD) were detected using corresponding commercial kits. Expressions of collagen-related and apoptosis-associated proteins in renal tissues were, respectively, evaluated by immunofluorescence and western blotting. Cell apoptosis was detected by TUNEL assay, and transporter expressions using western blotting. Followed by WFA, NRK-52E cells were treated with UA before evaluation of apoptosis and fibrosis. Results indicated that WFA ameliorated renal damage, improved kidney function, and decreased levels of creatinine, BUN, UA, and XOD in PO-induced hyperuricemic mice. Furthermore, WFA significantly prevented renal fibrosis and increased the expression of collagen-related proteins. Similarly, WFA markedly inhibited renal apoptosis, accompanied by changes of apoptosis-related proteins. Importantly, expression of transporters responsible for the secretion of organic anion transporter 1 (OAT1), OAT3, ATP-binding cassette subfamily G member 2 (ABCG2) was remarkably enhanced whereas that of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) was reduced in renal tissues of mice with hyperuricemia. In vitro study revealed that WFA notably ameliorated UA-induced cell fibrosis and apoptosis. Taken together, WFA improves kidney function by decreasing UA via regulation of XOD and transporter genes in renal tubular cells.
研究领域:
药理学
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肾病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2022
·
IF 7.419
Tianqiao Yong,Danling Liang,Chun Xiao,Longhua Huang,Shaodan Chen,Yizhen Xie,Xiong Gao,Qingping Wu,Huiping Hu,Xiangmin Li,Yuancao Liu,Manjun Cai
In this paper, we reported the hypouricemic effect of 2,4-dihydroxybenzoic acid methyl ester (DAE), a component of Ganoderma applanatum , in hyperuricemic mice through inhibiting XOD and down-regulating URAT1. Computationally, DAE showed a high similarity to allopurinol and depicted a high affinity in docking to XOD. In vitro , DAE exhibited an inhibitory effect against XOD. Importantly, DAE demonstrated a remarkable hypouricemic effect, decreasing serum uric acids (SUAs) of hyperuricemic mice (407 ± 31 μmol/L) to 195 ± 23, 145 ± 33 and 134 ± 16 μmol/L ( P < 0.01) at the doses of 20, 40, and 80 mg/kg with a dose-dependent manner and showing efficacies at 54–68 %, which were close to the efficacies of allopurinol (61 %) and benzbromarone (57 %). DAE depicted higher and negatively dose-independent urinary uric acids in comparison with that of the hyperuricemic control, implying DAE exerted an uricosuric effect and also a reduction effect on uric acid production. Unlike toxic allopurinol and benzbromarone, no general toxicity on body weights and no negative influence on liver, kidney, spleen and thymus were observed for DAE. Mechanistically, DAE inhibited XOD activities in vivo . Moreover, DAE up-regulated OAT1 and down-regulated GLUT9, URAT1 and CNT2. Overall, DAE may present a hypouricemic effect through inhibiting XOD and up-regulating OAT1 and down-regulating GLUT9, URAT1 and CNT2. This work provided novel insights into the hypouricemic effect of DAE and G. applanatum.
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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医学
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2022
·Vol. 13
·期 22
·11780-11793
·
IF 6.317
Yin Wan,Dengxiao Wang,Yuefeng Shen,Yanru Chen,Jin Qian,Guiming Fu
Background: Lactobacillus fermentation has become a typical food processing method with the development of the modern food industry. Aims: This study aimed to assess the effects of Lactobacillus acidophilus NCUF202.2 fermentation on Artemisia selengensis Turcz (AST) in relieving hyperuricemia (HUA) and the mechanisms involved. Results: The fermented Artemisia selengensis Turcz extracts (FASTE) could significantly increase the content of free polyphenol and enhance the inhibitory effect on xanthine oxidase (XOD) in vitro. The result of ultrafiltration coupled with UPLC-MS/MS screened out the components that might be combined with XOD in the caffeoylquinic acids (CQAs) of Artemisia selengensis Turcz extracts (ASTE) as 5-CQA, 3-CQA, 4-CQA, 1-CQA, 3,4-diCQA, 3,5-diCQA, 1,5-diCQA and 4,5-diCQA as well as caffeic acid (CA) of FASTE except the above. Our results also showed that ASTE and FASTE could alleviate HUA in rats. In contrast, FASTE had a better ability to reduce serum adenosine deaminase (ADA) activity than ASTE. Furthermore, FASTE could restore catalase (CAT) in HUA model rats in vivo, and superoxide dismutase (SOD) activity to a better degree, thereby inhibiting the production of excess malondialdehyde (MDA). Under the intervention of ASTE and FASTE, the levels of serum pro-inflammatory and anti-inflammatory factors in rats tended to be normal. However, FASTE could increase the expression of the uric acid secretion protein OAT1 and decrease the expression of reabsorption proteins URAT1 and GLUT9 in model rats, thereby reducing the serum uric acid (SUA) level in model rats. ASTE and FASTE can increase the abundance of beneficial bacteria, such as Bifidobacterium and Akkermansiaceae. Conclusion: Overall, part of diCQAs and CQAs was decomposed after fermentation. FASTE had a more substantial HUA-relieving effect than ASTE. It is expected to be applied to functional foods and contribute to the research and development of uric acid lowering functional foods.
研究领域:
食品科学
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药理学
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生物化学
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营养学
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2024
·Vol. 15
·期 11
·6068-6081
·
IF 5.1
Haonan Yu,Zhenyou Lou,Tingbo Wu,Xiaochun Wan,Haitao Huang,Yuanyuan Wu,Bo Li,Youying Tu,Puming He,Junsheng Liu
Epigallocatechin gallate (EGCG), a prominent bioactive compound found in tea, offers numerous health benefits. Previous studies have highlighted its potential in mitigating hyperuricemia. In this study, hyperuricemic mice induced by potassium oxonate (PO) were treated with EGCG or the anti-hyperuricemia medication allopurinol (AP) to investigate the mechanisms underlying their anti-hyperuricemic effects. The results demonstrated that both EGCG and AP significantly reduced serum uric acid (UA) levels. Further analysis revealed that EGCG promoted the expression of UA secretion transporter genes (Oat1 and Oct1) while inhibiting the expression of UA reabsorption transporter genes (Urat1 and Glut9) in the kidney. By 16S rDNA sequencing, EGCG, but not AP, was found to alter the composition of the gut microbiota. Notably, EGCG induced significant changes in the relative abundance of specific bacteria such as Lactobacillus, Faecalibaculum, and Bifidobacterium, which displayed high correlations with serum UA levels and UA-related gene expression. Metabolomic analysis suggested that EGCG-induced modifications in bacterial metabolites might contribute to the alleviation of hyperuricemia. Transcriptomic analysis of the intestinal epithelium identifies 191 differentially expressed genes (DEGs) in EGCG-treated mice, including 8 purine-related genes. This study elucidates the anti-hyperuricemic mechanisms of EGCG, particularly its influence on the gut microbiota and gene expression in the intestinal epithelium.
研究领域:
药理学
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微生物学
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分子生物学
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营养学
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转录组学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF FOOD BIOCHEMISTRY
·
2022
·Vol. 46
·期 7
·e14140
·
IF 3.654
Dongyin Yuan,Ling Lin,Yingqi Peng,Yang Zhou,Li Li,Wenjun Xiao,Zhihua Gong
Black tea, a traditional drink, can induce urination and quench thirst. Black brick tea with fungal growth, prepared by steaming, pressing, inducing fungal growth, and drying the black tea, is a new type of black tea with different sensory qualities and is suitable for storage. However, the effects of black brick tea with fungal growth on lowering uric acid are still unexplored. Therefore, the potassium oxonate was administered for 7 consecutive days to establish the hyperuricemic mice. Then allopurinol, black tea, and black brick tea with fungal growth were orally administered with hyperuricemic mice for 14 days. Serum uric acid levels, liver xanthine oxidase (XOD) and adenosine deaminase (ADA) activities, and expression of renal urate transporters and inflammatory response were detected. Compared to the model group, both types of black tea lowered serum uric acid by decreasing the uric acid production with inhibiting the activities of XOD and ADA, and increasing uric acid excretion because of downregulating urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) expressions, and upregulating organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3), and organic cation transporter 1 (OCT1) expressions. They could also improve renal injury by suppressing the activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, and nuclear factor-κB (NF-κB) signaling, thereby reducing renal proinflammatory cytokine levels. Compared with black tea, black brick tea with fungal growth with a higher content of theabrownins had a better effect on lowering serum uric acid. Practical applications Black tea accounts for approximately 78% of the total consumed tea in the world. Black brick tea with fungal growth is a new kind of black tea product with different sensory qualities and is suitable for storage. The study found that black brick tea with fungal growth is superior to black tea in reducing serum uric acid levels, which make a significant contribution to promote people’s health and stimulate the production and consumption of black brick tea with fungal growth. In addition, it provides a clue for future research to identify the effective components of black brick tea with fungal growth lowering uric acid.
研究领域:
药理学
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生物化学
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营养学
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动物科学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）