Frontiers in Pharmacology
·
2018
·
IF 3.831
Yong Tianqiao,Chen Shaodan,Xie Yizhen,Chen Diling,Su Jiyan,Shuai Ou,Jiao Chunwei,Zuo Dan
Ganoderma applanatum (G. applanatum) dispels wind to eliminate dampness and exhibited nephron- and liver-protective effects as noted in Chinese herbal classic literature; it might also affect hyperuricemia. Therefore, we examined the hypouricemia effects and mechanisms underlying G. applanatum on chemical-induced hyperuricemia in mice. Ethanol (GAE) and water (GAW) extracts were prepared by extracting G. applanatum in ethanol (GAE), followed by bathing the remains in water to yield GAW. GAE and GAW were administered orally at different doses to hyperuricemia mice, while allopurinol and benzbromarone served as positive controls. Both GAE and GAW showed remarkable hypouricemia activities, rendering a substantial decline in the SUA (serum uric acid) level in hyperuricemia control (P < 0.01). Moreover, the urine uric acid (UUA) levels were enhanced by GAE and GAW. In contrast to the evident renal toxicity of allopurinol, GAE and GAW did not show a distinct renal toxicity. Almost no suppressing effect was observed on the XOD activities. However, compared to the hyperuricemia control, OAT1 was elevated remarkably in mice drugged with GAE and GAW, while GLUT9 was significantly decreased. Similar to benzbromarone, GAE decreased the URAT1 protein levels significantly (P < 0.01), while GAW did not display a similar effect. GAE and GAW downregulated the level of CNT2 proteins in the gastrointestinal tract of hyperuricemia mice. Thus, G. applanatum produced outstanding hypouricemic effects, mediated by renal OAT1, GLUT9, and URAT1 and gastrointestinal CNT2 that might elevate urine uric secretions and decline in the absorption of purine in the gastrointestinal tracts. G. applanatum showed little negative influence on inner organs. By docking screening, four top-ranked compounds were identified that necessitated further investigation.Compounds: potassium oxonate, hypoxanthine, allopurinol, benzbromarone.
研究领域:
药理学
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医学
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分子生物学
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DOI
PubMed
高影响因子
Biomaterials Science
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2022
·Vol. 11
·期 5
·1704-1713
·
IF 7.59
Rui Wang,Han Wang,Guohua Jiang,Yanfang Sun,Tianqi Liu,Lei Nie,Amin Shavandi,Khaydar E. Yunusov,Uladzislau E. Aharodnikau,Sergey O. Solomevich
Allopurinol (AP) is widely used to treat hyperuricemia which may cause severe side effects upon oral administration. Alternative means for the treatment of hyperuricemia are demanded to simultaneously facilitate drug absorption, patient compliance, and fewer side effects. In this study, a new polymer microneedle (MN) system was developed for the transdermal delivery of AP to acute hyperuricemic mice. This study aims to achieve the controllable regulation of serum uric acid (SUA) levels with fewer side effects compared with oral administration. The matrix of polymer MNs consisted of polyvinylpyrrolidone (PVP) and polycaprolactone (PCL), in which the rapid dissolution of PVP offers a rapid dissolution of AP into the blood and the biodegradability of PCL resulting in a sustainable drug release behavior. An in vivo study demonstrated that the AP-loaded MN system can effectively reduce the SUA levels as oral administration with lower side effects, which will be conducive to reducing the adverse reactions and improving the bioavailability of AP. This MN-mediated strategy can facilitate transcutaneous hyperuricemia treatment and provide a new alternative for the exploration of clinical treatment of hyperuricemia and improvement of patient compliance.
研究领域:
药剂学
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药物递送系统
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药理学
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产品关联
DOI
PubMed
高影响因子
Gut Microbes
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2024
·
IF 12.2
Zhen-Ping Zou,Ju-Ling Li,Yi-Fan Zhang,Ying Zhou,Bang-Ce Ye
Hyperuricemia, a prevalent metabolic disorder, poses a susceptibility to various complications. The conventional pharmacotherapeutic approaches for hyperuricemia often entail notable adverse effects, posing substantial clinical challenges. Hence, the imperative lies in the development of novel, safe and effective strategies for preventing and treating hyperuricemia. Here, we developed a probiotic Escherichia coli Nissle 1917 strain, designated as YES301, which contains a rationally designed xanthine importer XanQ, enabling efficient uptake of xanthine and hypoxanthine, consequently leading to reduced serum uric acid concentrations and amelioration of renal impairments in a murine model of hyperuricemia. Importantly, YES301 exhibited a therapeutic efficacy comparable to allopurinol, a conventional uric acid-lowering agent, and manifesting fewer adverse effects and enhanced biosafety. These findings highlight the promising potential of engineered probiotics in the management of hyperuricemia through reducing intestinal purine levels.
研究领域:
代谢紊乱
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药理学
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微生物学
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生物技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
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2016
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IF 3.973
Ran Zhao,Dong Chen,Hualing Wu
To investigate the effects of Pu-erh ripened tea on lowering uric acid levels and identify its possible mechanisms, three different doses of the tea, with allopurinol as a positive control, were administered intragastrically to hyperuricemic mice. Hyperuricemia was induced in the mice by oral administration of potassium oxonate for 7 days. Serum levels of uric acid, liver xanthine oxidase (XOD) and adenosine deaminase (ADA) activities, and expression of renal mURAT1, mGLUT9, mOAT1 and mOCT1 protein and mRNA were measured. Pu-erh ripened tea, at all doses, significantly lowered serum uric acid levels. At the high and medium doses, it also markedly inhibited liver XOD and ADA activities. Furthermore, mURAT1 and mGLUT9 expression levels were significantly down-regulated by Pu-erh ripened tea treatment. These results suggested that Pu-erh ripened tea can resist to hyperuricemia, possibly by inhibiting, concurrently, uric acid production and renal urate reabsorption.
研究领域:
药理学
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生物化学
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医学
✓ 已验证
产品关联
DOI
高影响因子
Food Quality and Safety
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2021
·
IF 3.102
Xie Jiahong,Cui Haoxin,Xu Yang,Xie Lianghua,Chen Wei
ObjectivesThis study was conducted to investigate the xanthine oxidase (XO) inhibitory activities of 18 monomeric anthocyanins from berry fruits and roselle, and to illustrate the underlying mechanism of the most active anthocyanin delphinidin-3-O-sambubioside.Materials and MethodsEighteen monomeric anthocyanins were prepared and purified in our laboratory. The inhibitory properties of anthocyanins were investigated by in vitro inhibitory activity studies and fluorescence quenching studies; the inhibitory mechanism was explored through kinetic studies, fluorescence quenching studies, circular dichroism analysis and computational docking simulations.ResultsXO inhibitory activities of anthocyanins were related to the structures of B rings and glycosides. Among all the tested anthocyanins, delphinidin-3-O-sambubioside showed the most potent inhibitory activity with an IC50 of 17.1 μM, which was comparable to the positive control allopurinol. Spectroscopic results revealed that delphinidin-3-O-sambubioside could spontaneously interact with XO and induce conformational changes. Computational docking study indicated that delphinidin-3-O-sambubioside could bind to XO with a proper orientation, stably formed π–π interactions and hydrogen bonds with key residues, thus preventing the substrate from entering the active pocket.ConclusionsIn brief, our study identified delphinidin-3-O-sambubioside as a potent XO inhibitor from natural anthocyanins, which is potentially applicable for prevention and treatment of hyperuricemia.
研究领域:
药理学
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生物化学
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天然产物化学
✓ 已验证
产品关联
DOI
高影响因子
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
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2023
·
IF 8.7
Liu Yang,Hao Wu,Congcong Luo,Yang Zhao,Rongbo Dai,Zhiqing Li,Xu Zhang,Ze Gong,Zeyu Cai,Yicong Shen,Fang Yu,Wei Li,Hongmei Zhao,Tao Zhang,Junming Zhu,Yi Fu,Jing Wang,Wei Kong
Background:Thoracic aortic aneurysm and dissection (TAAD) is a highly lethal vascular disease without effective drug therapy. Whether elevated serum concentrations of uric acid are involved in TAAD development remains unclear.Methods:Serum uric acid levels were detected in different TAAD mouse models and patients. The urate-lowering drug allopurinol was administered in the drinking water of TAAD mice. Adenine diet–induced mice were established to investigate the role of hyperuricemia in TAAD formation and RNA-sequencing of thoracic aortas from these mice was performed.Results:We found serum uric acid levels were elevated in various mouse TAAD models, including mice fed a β-aminopropionitrile diet, Marfan mice with fibrillin-1 haploinsufficiency (Fbn1C1041G/+), and ApoE−/− mice infused with Ang II (angiotensin II), as well as in patients with TAAD. Administration of urate-lowering drug allopurinol in the drinking water significantly alleviated TAAD formation in β-aminopropionitrile–treated mice, Fbn1C1041G/+ mice, and Ang II–infused ApoE−/− mice. Moreover, an adenine diet was used to induce hyperuricemia in mice. Intriguingly, a 4-week adenine diet feeding directly induced TAAD formation characterized by increased maximal thoracic aortic diameters and severe elastin degradation, which were ameliorated by allopurinol. Unbiased RNA-sequencing in mouse thoracic aortas suggested that FcγR (Fc gamma receptor) was upregulated upon adenine diet, but reciprocally repressed by allopurinol. Mechanistically, hyperuricemia activated FcγR-mediated ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation to induce macrophage inflammation and TAAD development, which was abrogated by allopurinol or FcγR deficiency.Conclusions:This study uncovered an important and previously unrecognized role of hyperuricemia in mediating the pathogenesis of TAAD, and uric acid–lowering drug may represent a promising therapeutic approach for TAAD.
研究领域:
心血管疾病
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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
Food & Function
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2021
·Vol. 12
·期 15
·7054-7067
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IF 5.396
Caixin Ni,Xin Li,Linlin Wang,Xiu Li,Jianxin Zhao,Hao Zhang,Gang Wang,Wei Chen
Globally, the incidence of hyperuricaemia is steadily increasing. The evidence increasingly suggests an association between hyperuricaemia and the gut microbiota, which may enable the development of a novel therapeutic approach. We studied the effects of treatment with lactic acid bacteria (LAB) on hyperuricaemia and their potential underlying mechanisms. A mouse model of hyperuricaemia was generated by oral gavage with hypoxanthine and intraperitoneal injections of potassium oxonate for 2 weeks. The anti-hyperuricaemic activities of 10 LAB strains relative to allopurinol as a positive drug control were investigated in the mouse model. Lactobacillus rhamnosus R31, L. rhamnosus R28-1 and L. reuteri L20M3 effectively reduced the uric acid (UA) concentrations in serum and urine and the xanthine oxidase (XOD) activity levels in serum and hepatic tissue in mice with hyperuricaemia. These strains also reversed the elevated lipopolysaccharide (LPS) concentration, hepatic inflammation and slight renal injury associated with hyperuricaemia. A correlation analysis revealed that UA-reducing LAB strains promoted short-chain fatty acid (SCFA) production to suppress serum and hepatic XOD activity by increasing the abundances of SCFA production-related gut bacterial taxa. However, the UA-reducing effects of LAB strains might not be mediated by purine degradation. In summary, L. rhamnosus R31, L. rhamnosus R28-1 and L. reuteri L20M3 relieved hyperuricaemia in our mouse model by promoting SCFA production in a purine degradation-independent manner. Our findings suggest a novel therapeutic approach involving LAB strains for hyperuricaemia.
研究领域:
微生物学
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药理学
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营养学
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代谢学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Jiaqi Wen,Shuling Chen,Le Deng,Xinru Chen,Xiaoyu Jiang,Xing Hu,Deming Gong,Guowen Zhang
The development of natural xanthine oxidase (XO) inhibitors is an effective strategy for the treatment of hyperuricemia. In this study, the inhibition mechanism of phloretin on XO and its joint inhibition with clinical drugs (allopurinol and febuxostat) were investigated, using multispectroscopic and molecular simulation techniques. The results showed that phloretin reversibly inhibited XO in a mixed type with an IC 50 value of 31.83 ± 0.32 μM. Phloretin quenched the fluorescence of XO with a static mechanism and hydrophobic interactions were the key binding force of phloretin binding to XO. Furthermore, the interaction between phloretin and XO resulted in a more relaxed structure and less stable of the enzyme with a reduction in the α-helix content from 21.5% to 11.3%. The heatmap analysis showed that a combination of phloretin (15 μM) and allopurinol (10 μM) or phloretin (30 μM) and febuxostat (0.01 μM) exhibited the strongest synergistic effect on XO inhibition in a mixed manner. The combination of phloretin and allopurinol/febuxostat enhanced the binding affinity with XO compared to the inhibitors individually. Molecular docking indicated that phloretin, allopurinol and febuxostat bound to different sites of XO to produce a synergistic inhibition by preventing substrate access to the Mo activity center and affecting electron transfer. This study may provide theoretical references for the development of phloretin and its formulation with clinical drugs as uric acid-lowering food functional factor or drug.
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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药物开发
✓ 已验证
产品关联
DOI
高影响因子
Journal of Functional Foods
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2018
·
IF 3.47
Ni Zeng,Guowen Zhang,Xing Hu,Junhui Pan,Zhisheng Zhou,Deming Gong
Suppression of xanthine oxidase (XO) may contribute to control hyperuricemia and gout. In this study, baicalein and baicalin, two dietary flavones, were found to inhibit the formation of uric acid and generation of superoxide anion (O 2 − ) catalysed by XO through interaction with primary amino acid residues located in flavin adenine dinucleotides center of XO. Baicalein or baicalin binding to XO mainly facilitated by hydrophobic interactions and hydrogen bonds resulted in more compact of XO structure. The concentration profiles and pure spectra of the components extracted from highly overlapping spectral signal by multivariate curve resolution–alternating least squares chemometrics algorithm confirmed the formation of complexes and monitored the reaction kinetics process between XO and these flavones. Furthermore, the isobolographic analysis found that baicalein or baicalin exhibited a moderate synergy on the inhibition of XO when it combined with allopurinol as well as the joint use of baicalein and baicalin.
研究领域:
药理学
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生物化学
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医学
✓ 已验证
产品关联
DOI
高影响因子
TOXICOLOGY IN VITRO
·
2024
·
IF 2.6
Jia-hong Liang,Xiao-lei Yi,Jia-min Gong,Zuo Du
Gout is an immune-metabolic disease that frequently coexists with multiple comorbidities such as chronic kidney disease, cardiovascular disease and metabolic syndrome, therefore, it is often treated in combination with these complications. The present study aimed to evaluate the inhibitory effect of antigout drugs (allopurinol, febuxostat, topiroxostat, benzbromarone, lesinurad and probenecid) on the activity of the crucial phase I drug-metabolizing enzymes, carboxylesterases (CESs). 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) and fluorescein diacetate (FD) were utilized as the probe reactions to determine the activity of CES1 and CES2, respectively, through in vitro culturing with human liver microsomes. Benzbromarone and lesinurad exhibited strong inhibition towards CESs with Ki values of 2.16 and 5.15 μM for benzbromarone towards CES1 and CES2, respectively, and 2.94 μM for lesinurad towards CES2. In vitro-in vivo extrapolation (IVIVE) indicated that benzbromarone and lesinurad might disturb the metabolic hydrolysis of clinical drugs in vivo by inhibiting CESs. In silico docking showed that hydrogen bonds and hydrophobic interactions contributed to the intermolecular interactions of antigout drugs on CESs. Therefore, vigilant monitoring of potential drug-drug interactions (DDIs) is imperative when co-administering antigout drugs in clinical practice.
研究领域:
药理学
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临床药理学
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药物代谢
✓ 已验证
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
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
·
生物化学
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分子生物学
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医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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