AMERICAN JOURNAL OF CHINESE MEDICINE
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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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2024
·
IF 4.5
Fengxin Zheng,Jiale Ke,Shiqin Lin,Wenjie Ye,Zhenkun Wu,Yuexin Xu,Suiqing Mai,Yishuang Chen,Zitao Guo,Huazhong Hu,Shuqin Zhang,Jianxin Pang,Qun Zhang,Zean Zhao
Inhibition of human concentrative nucleoside transporter 2 (CNT2) could suppress increases in serum urate levels derived from dietary purines. However, the structural basis for substrate recognition of CNT2 is still unknown and only a few inhibitors have been reported. In this study, a homology model of CNT2 was constructed and residues T315, E316, N426, N491, E492, F536 and N538 were identified as binding sites for adenosine through site-directed mutagenesis and a 3 H-adenosine uptake assay. To explore potential CNT2 inhibitors, a database containing 4704 saccharides and glycosides was constructed, followed by high-throughput virtual screening. The top 20 compounds with the highest docking scores were then evaluated their in vitro activity. Among them, cyanidin-3-O-galactoside (Cy3Gal) demonstrated the most potent inhibitory activity against CNT2, exhibiting an IC 50 value of 9.40 μM. Docking analysis revealed that residues M314, T315, T347, N422, F536 and S541 contributed to a strong binding affinity with Cy3Gal. In addition, Cy3Gal exhibited minimal inhibitory effects on CNT3 and equilibrative nucleoside transporters (ENTs) in vitro . At doses of 5–20 mg/kg, Cy3Gal effectively reduced serum and urine levels of uric acid and adenosine in vivo . The CCK-8 assay revealed that Cy3Gal displayed minimal cytotoxicity to mTEC and hIEC cells at a concentration of 100 μM. The serum CR and BUN levels indicate that Cy3Gal does not exhibit any apparent renal toxicity compared to lesinurad and allopurinol. HE examination showed no noticeable pathological changes in the kidneys or colons after treatment with Cy3Gal. In summary, Cy3Gal could be a CNT2 inhibitor with favorable drugability for the treatment of hyperuricemia.
研究领域:
药理学
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分子生物学
·
药物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Suiqing Mai,Jiale Ke,Shiqin Lin,Rongrong Huang,Fengxin Zheng,He Jiao,Hong Wang,Shuqin Zhang,Mengying Mao,Qiuping Li,Zean Zhao,Jianxin Pang,Qun Zhang
A high-purine diet is an important factor in the development of hyperuricemia (HUA), in which the intestinal tract is the main site of dietary purine absorption. Inhibition of intestinal concentrative nucleoside transporter 2 (CNT2) can inhibit dietary purine-induced elevation of serum uric acid (sUA) levels. However, there is a lack of research on CNT2 inhibitors for the treatment of HUA. By using high throughput virtual screening from an in-house natural product database, the natural active component 5-methylvisammioside (MeV) in Saposhnikovia divaricata (Turcz.) Schischk was predicted to be an effective CNT2 inhibitor with the highest docking score. In vitro , MeV showed the strongest inhibitory activity against CNT2, with IC 50 value of 11.22 ± 2.18 μM. Moreover, MeV showed little or almost no inhibitory effect on other nucleoside transporters CNT3 and equilibrative nucleoside transporters (ENTs), as well as on uric acid (UA) transporter-related targets. In vivo , MeV significantly reduced sUA, inhibited adenosine uptake, and had an ameliorative effect on pathological changes in the liver, kidney, and intestinal tract. Moreover, MeV improved serum and intestinal indices related to inflammation and oxidative stress in mice, reduced intestinal permeability. Through our further study, we found that MeV inhibited the activation of reactive oxygen species (ROS) and NF-κB P65, reduced the production of the NOD-like receptor protein 3 (NLRP3) inflammasome, and improved intestinal injury in a high UA environment. The study suggests that MeV is a potent CNT2 inhibitor for the treatment of HUA and also protects intestinal function by inhibiting the ROS/NF-κB/NLRP3 pathway.
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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药物化学
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营养学
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胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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
·
医学
·
分子生物学
✓ 已验证
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
·
分子生物学
·
医学
✓ 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）