BIOORGANIC CHEMISTRY
·
2024
·
IF 4.5
Fengxin Zheng,Suiqing Mai,Xiaolin Cen,Pei Zhao,Wenjie Ye,Jiale Ke,Shiqin Lin,Huazhong Hu,Zitao Guo,Shuqin Zhang,Hui Liao,Ting Wu,Yuanxin Tian,Qun Zhang,Jianxin Pang,Zean Zhao
The development of XOD/URAT1 dual target inhibitors has emerged as a promising therapeutic strategy for the management of hyperuricemia. Here, through virtual screening, we have identified digallic acid as a novel dual target inhibitor of XOD/URAT1 and subsequently evaluated its pharmacological properties, pharmacokinetics, and toxicities. Digallic acid inhibited URAT1 with an IC 50 of 5.34 ± 0.65 μM, which is less potent than benzbromarone (2.01 ± 0.36 μM) but more potent than lesinurad (10.36 ± 1.23 μM). Docking and mutation analysis indicated that residues S35, F241 and R477 of URAT1 confer a high affinity for digallic acid. Digallic acid inhibited XOD with an IC 50 of 1.04 ± 0.23 μM. Its metabolic product, gallic acid, inhibited XOD with an IC 50 of 0.91 ± 0.14 μM. Enzyme kinetic studies indicated that both digallic acid and gallic acid act as mixed-type XOD inhibitors. It shares the same binding mode as digallic acid, and residues E802, R880, F914, T1010, N768 and F1009 contribute to their high affinity. The anion group (carboxyl) of digallic acid contribute significantly to its inhibition activity on both XOD and URAT1 as indicated by docking analysis. Remarkably, at a dosage of 10 mg/kg in vivo, digallic acid exhibited a stronger urate-lowering and uricosuric effect compared to the positive drug benzbromarone and lesinurad. Pharmacokinetic study indicated that digallic acid can be hydrolyzed into gallic acid in vivo and has a t 1/2 of 0.77 ± 0.10 h. Further toxicity evaluation indicated that digallic acid exhibited no obvious renal toxicity, as reflected by CCK-8, biochemical analysis (CR and BUN) and HE examination. The findings of our study can provide valuable insights for the development of XOD/URAT1 dual target inhibitors, and digallic acid deserves further investigation as a potential anti-hyperuricemic drug.
研究领域:
药理学
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药物化学
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药物发现
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DOI
PubMed
高影响因子
Pharmaceuticals
·
2026
·Vol. 19
·期 3
·490
·
IF 5.7
Hailong Zhang,Jiaxin Huang,Wenji Yang,Wenhu Zhou,Jinsong Ding,Qianbin Li,Gaoyun Hu
Background : Hyperuricemia (HUA) is a metabolic disorder that severely threatens human health. Chronic uric acid (UA) overload promotes the progression of tubulointerstitial fibrosis (TIF), leading to impaired UA excretion. Our previous studies identified HIPK2 inhibitor XRF-1021, which exhibits robust anti-TIF activity and lowers UA levels in vivo. This study aimed to elucidate its UA-lowering mechanism and therapeutic potential for HUA. Methods : Uricase and xanthine oxidase (XOD) assays were performed to assess effects on UA degradation/production. HEK293T cells transiently expressing UA transporters and gene-knockdown rats were used to evaluate transporter inhibition, while HK-2 cells were analyzed by Western blot. Pharmacokinetics were characterized in rats. Efficacy was tested in potassium oxonate-induced acute HUA rats, diet/adenine-induced chronic HUA quails, and adenine-induced mice with HUA secondary to TIF. Maximum tolerated dose and long-term toxicity were assessed in rats. Results : XRF-1021 neither activated uricase nor inhibited XOD, indicating no direct effect on UA catabolism or synthesis. Instead, XRF-1021 inhibited URAT1 and GLUT9, reducing renal UA reabsorption, while sparing OAT3, OAT4, and ABCG2 activity and upregulating OAT3 and NPT4, suggesting minimal risk of disrupting drug or uremic toxin handling. XRF-1021 showed dose-dependent systemic exposure in rats, lowered serum UA, and provided renal protection in vivo. LD 50 values were 2345.4 mg/kg (male) and 1078.9 mg/kg (female), with no obvious toxicity after long-term dosing. Conclusions : XRF-1021 lowers UA by inhibiting URAT1 and GLUT9 to enhance renal UA excretion and provides kidney protection, supporting XRF-1021 as a promising candidate for HUA therapy.
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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
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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
Journal of Pharmaceutical Analysis
·
2025
·
IF 8.9
Shiquan Zheng,Jiale Ke,Hanren Chen,Huaze Shao,Fengxin Zheng,Runhui Zhang,Zean Zhao,Jianxin Pang,Lihong Liu
The lack of a cell-based screening method limits urate-lowering drug development. A novel method combining aptamer sensor array (ASA), exonuclease III (Exo III)- powered 3D DNA walker (DW), and linear discriminant analysis (LDA) was developed for detecting uric acid (UA) in cell lysates, referred to as ASA–Exo III-DW–LDA. Three aptamers (Apts) with different affinities for UA and its structurally similar compound, xanthine (Xan), were used to design the ASA. The combination of ASA and Exo III-DW enabled the detection of UA at the picomolar level, whereas LDA was employed to differentiate UA signals from the mixed signals of UA and Xan. Significantly, Pearson correlation analysis revealed a strong correlation between our method and the 14 C radioactive labeling method for urate anion exchanger 1 (URAT1) inhibitors, with r = 0.9880 for lesinurad and r = 0.9777 for benzbromarone. Using our method, kaempferol was identified as a promising hit compound for inhibiting the URAT1, because of its low half-maximal inhibitory concentration (IC 50 ) (18.96 μM) low toxicity in mouse renal tubular epithelial cells (mTECs), and significant urate-lowering effect in hyperuricemic mice at 5 mg/kg. Overall, this method is sensitive, cost-effective and safe, offering a novel strategy for routine urate-lowering drug screening in standard laboratories.
研究领域:
生物化学
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药物开发
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分子生物学
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DOI
PubMed
高影响因子
DRUG AND CHEMICAL TOXICOLOGY
·
2025
·
IF 1.9
Yongxiao Huang,Caina Jiang,Fangyao Li,Xianli Ma
As a commonly used flame retardant in numerous products, it is inevitable that tris(2-chloroethyl)phosphate (TCEP) is released into the surrounding environment during its use. This process gives rise to potential environmental concerns that must be addressed. In recent years, there has been significant interest in the role of TCEP in the development of hyperuricemia (HUA). However, the specific mechanisms by which TCEP contributes to this condition remain to be fully elucidated. In this study, we have employed a combination of network toxicology and in vitro experiments to investigate the potential effects of TCEP on HUA and its mechanism of action. Through systematic analysis of GeneCards, OMIM, Swiss Target Prediction, and CHEMBL databases, a total of 242 TCEP-induced HUA targets were identified. Utilizing the STRING and DAVID databases further elucidated the core targets and associated signaling pathways of TCEP in relation to HUA. The molecular docking assay results demonstrated that TCEP exhibits binding activity with the selected targets. In vitro, our findings revealed that TCEP exacerbates HUA by amplifying the inflammatory response and upregulating the mRNA expression levels of GLUT9 and URAT1. The present study provides a new perspective and theoretical basis for the in-depth understanding of the molecular mechanism of TCEP affecting HUA, and helps to further understand the pathogenesis of HUA and the role of environmental factors.
研究领域:
环境毒理学
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分子生物学
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药理学
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生物信息学
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DOI
PubMed
高影响因子
Journal of Functional Foods
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2019
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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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DOI
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2021
·
IF 6.514
Zean Zhao,Jin Liu,Peihua Kuang,Jian Luo,Goverdhan Surineni,Xiaolin Cen,Ting Wu,Ying Cao,Pingzheng Zhou,Jianxin Pang,Qun Zhang,Jianjun Chen
Verinurad (RDEA3170) is a selective URAT1 inhibitor under investigation for the treatment of gout and hyperuricemia . In an effort to further improve the pharmacodynamics/pharmacokinetics of verinurad and to increase the structural diversity, we designed novel verinurad analogs by introducing a linker (e.g. aminomethyl, amino or oxygen) between the naphthalene and the pyridine ring to increase the flexibility. These compounds were synthesized and tested for their in vitro URAT1-inhibitory activity. Most compounds exhibited potent inhibitory activities against URAT1 with IC 50 values ranging from 0.24 μM to 16.35 μM. Among them, compound KPH2f exhibited the highest URAT1-inhibitory activity with IC 50 of 0.24 μM, comparable to that of verinurad (IC 50 = 0.17 μM). KPH2f also inhibited GLUT9 with an IC 50 value of 9.37 ± 7.10 μM, indicating the dual URAT1/GLUT9 targeting capability. In addition, KPH2f showed little effects on OAT1 and ABCG2 , and thus was unlikely to cause OAT1/ABCG2-mediated drug-drug interactions and/or to neutralize the uricosuric effects of URAT1/GLUT9 inhibitors. Importantly, KPH2f (10 mg/kg) was equally effective in reducing serum uric acid levels and exhibited higher uricosuric effects in a mice hyperuricemia model, as compared to verinurad (10 mg/kg). Furthermore, KPH2f demonstrated favorable pharmacokinetic properties with an oral bioavailability of 30.13%, clearly better than that of verinurad (21.47%). Moreover, KPH2f presented benign safety profiles without causing hERG toxicity, cytotoxicity in vitro (lower than verinurad), and renal damage in vivo . Collectively, these results suggest that KPH2f represents a novel, safe and effective dual URAT1/GLUT9 inhibitor with improved druggabilities and is worthy of further investigation as an anti-hyperuricemic drug candidate.
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PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Yong-jun Chen,Zi-tao Guo,Hai-qiao Chen,Shi-fan Zhang,Ying-xia Bao,Zhoufan Xie,Jia-le Ke,Wen-jie Ye,Jia-cheng Liang,Jia-chen Chen,Ning Li,Feng-xin Zheng,Hui Liao,Ting Wu,Jian-xin Pang
Long-term hyperuricemia can induce kidney damage, clinically referred to as hyperuricemic nephropathy (HN), which is characterized by renal fibrosis, inflammation, and oxidative stress. However, currently used uric acid-lowering drugs are not capable of protecting the kidneys from damage. Therefore, uric acid-lowering drugs that can also protect the kidneys are urgently needed. In this study, we first discovered that salinomycin, an antibiotic, can regulate uric acid homeostasis and ameliorate kidney damage in mice with HN. Mechanistically, salinomycin inhibited serum and hepatic xanthine oxidase (XOD) activities and downregulated renal urate transporter 1 (URAT1) expression and transport activity, thus exerting uric acid-lowering effects in mice with HN. Furthermore, we found that salinomycin promoted p-NRF2 Ser40 expression, resulting in increased nuclear translocation of NRF2 and activation of NRF2. More importantly, salinomycin affected the gut microbiota and promoted the generation of short-chain fatty acids (SCFAs) in mice with HN. In conclusion, our results revealed that salinomycin maintains uric acid homeostasis and alleviates kidney injury in mice with HN by multiple mechanisms, suggesting that salinomycin might be a desirable candidate for HN treatment in the clinic.
研究领域:
药理学
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肾病学
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微生物学
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分子生物学
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PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Cheng Cao,Mubin Sun,Jiabao Li,Zhenyu Yuan,Yuwei Gu,Yufan Shao,Lisheng Wang,Xiaohua Jin,Yijie Cheng,Bo Fan
Urate transporter 1 (URAT1, encoded by SLC22A12 ) is a key mediator of renal urate reabsorption and an important pharmacological target for urate-related disorders. Sodium butyrate (BuNa), a gut microbiota derived short-chain fatty acid, has been implicated in host metabolic regulation, but its role in renal urate transport remains unclear. Here, using molecular docking, cellular thermal shift assays, immunoprecipitation-mass spectrometry and multi-omics analyses, we identified free fatty acid receptor 2 (FFAR2) as a direct target of BuNa in renal proximal tubular HK2 cells . BuNa binding upregulated FFAR2 and promoted URAT1 expression and urate uptake via an FFAR2-dependent pathway. Mechanistically, BuNa/FFAR2 signaling acts via GNAQ to activate PLCβ, generating diacylglycerol and engaging a PKC-dependent p38 MAPK/ELK1 cascade that upregulates arrestin beta 2 (ARRB2). ARRB2 directly binds to IκB, preventing its phosphorylation-dependent degradation, thereby stabilizing IκB and inhibiting NF-κB nuclear translocation. Within the SLC22A12 promoter, NF-κB (RELA/p50) and hepatocyte nuclear factor 1 beta (HNF1β) compete for overlapping binding sites. By blocking NF-κB nuclear entry, BuNa relieves this competition, permitting HNF1β-driven SLC22A12 transcription. Thus, BuNa enhances URAT1-mediated urate reabsorption in HK2 cells via an FFAR2/GNAQ/p38 MAPK/ELK1/ARRB2 axis that stabilizes IκB, suppresses NF-κB, and relieves the competitive binding between NF-κB and HNF1β on the SLC22A12 promoter. These findings establish a previously unrecognized gut microbiota–kidney axis linking microbial BuNa to renal urate homeostasis through a novel transcriptional regulatory circuit.
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高影响因子
Foods
·
2025
·Vol. 14
·期 3
·524
·
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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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
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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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DOI
PubMed
高影响因子
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