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
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Jianan Yang,Tonglian Jiang,Xun Lu,Xiang li,Xuling Zhou,Xinxin Guo,Chengxin Ma,Xiaobei Xie,Dongxiao Li,Siqi Yu,Jiayi An,Binghai Zhao,Hongzhi Li
Hyperuricemia is a known risk factor for chronic kidney disease (CKD) and subsequent renal fibrosis. N6-methyladenosine (m6A) is the most prevalent chemical modification in eukaryotic mRNAs and has been implicated in various diseases. However, its role in hyperuricemic nephropathy (HN) remains unclear. This study investigated the involvement of the methylase METTL14 in HN pathogenesis. Our in vitro and in vivo function experiments demonstrated that METTL14 plays a crucial role in HN. In mouse models of uric acid (UA)-induced renal injury, we detected impaired kidney function, increased renal interstitial fibrosis, and significantly decreased m6A methylation levels in renal tissues. Treatment with benzbromarone, a UA-lowering drug, alleviated renal injury, restored m6A methylation levels, and upregulated METTL14 expression. Cellular experiments showed that METTL14 overexpression attenuated high UA-induced fibrosis in renal tubular epithelial cells. This overexpression significantly decreases the expression of GLUT9, a key protein involved in UA transport, leading to reduced UA reabsorption. Additionally, MeRIP-qPCR and dual-luciferase reporter gene experiments further demonstrated that METTL14 overexpression enhanced Glut9 mRNA m6A methylation modification, accelerating its degradation and decreasing expression levels. Thus, METTL14-mediated RNA m6A modification plays a role in the renal tubular epithelial cell damage induced by high UA, by regulating Glut9 mRNA post-transcriptionally. These findings provide valuable insights for the diagnosis and development of therapeutic drugs for HN.
研究领域:
肾病学
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分子生物学
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表观遗传学
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
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IF 5.7
Lu Li,Kunlu Zhao,Jian Luo,Jinhong Tian,Fengxin Zheng,Xueman Lin,Zijun Xie,Heyang Jiang,Yongmei Li,Zean Zhao,Ting Wu,Jianxin Pang
Uncontrolled hyperuricemia often leads to the development of hyperuricemic nephropathy (HN), characterized by excessive inflammation and oxidative stress. Piperine, a cinnamic acid alkaloid, possesses various pharmacological activities, such as antioxidant and anti-inflammatory effects. In this study, we intended to investigate the protective effects of piperine on adenine and potassium oxonate-induced HN mice and a uric-acid-induced injury model in renal tubular epithelial cells (mRTECs). We observed that treatment with piperine for 3 weeks significantly reduced serum uric acid levels and reversed kidney function impairment in mice with HN. Piperine (5 μM) alleviated uric acid-induced damage in mRTECs. Moreover, piperine inhibited transporter expression and dose-dependently inhibited the activity of both transporters. The results revealed that piperine regulated the AKT/mTOR signaling pathway both in vivo and in vitro. Overall, piperine inhibits URAT1/GLUT9 and ameliorates HN by inhibiting the AKT/mTOR pathway, making it a promising candidate for patients with HN.
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
PHYTOMEDICINE
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2021
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IF 5.34
Yongmei Li,Zean Zhao,Jian Luo,Yanqing Jiang,Lu Li,Yanyu Chen,Leqi Zhang,Qinghua Huang,Ying Cao,Pingzheng Zhou,Ting Wu,Jianxin Pang
Background Hyperuricemia (HUA) is characterized by abnormal serum uric acid (UA) levels and demonstrated to be involved in renal injury leading to hyperuricemic nephropathy (HN). Apigenin (API), a flavonoid naturally present in tea, berries, fruits, and vegetables, exhibits various biological functions, such as antioxidant and anti-inflammatory activity. Purpose To investigate the effect of API treatment in HN and to reveal its underlying mechanisms. Methods The mice with HN were induced by potassium oxonate intraperitoneally and orally administered for two weeks. The effects of API on renal function, inflammation, fibrosis, and uric acid (UA) metabolism in mice with HN were evaluated. The effects of API on urate transporters were further examined in vitro . Results The mice with HN exhibited abnormal renal urate excretion and renal dysfunction accompanied by increased renal inflammation and fibrosis. In contrast, API reduced the levels of serum UA, serum creatinine (CRE), blood urea nitrogen (BUN) and renal inflammatory factors in mice with HN. Besides, API ameliorated the renal fibrosis via Wnt/β-catenin pathway suppression. Furthermore, API potently promoted urinary UA excretion and inhibited renal urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in mice with HN. In vitro , API competitively inhibited URAT1 and GLUT9 in a dose-dependent manner, with IC 50 values of 0.64 ± 0.14 μM and 2.63 ± 0.69 μM, respectively. Conclusions API could effectively attenuate HN through co-inhibiting UA reabsorption and Wnt/β-catenin pathway, and thus it might be a potential therapy to HN.
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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PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2021
·Vol. 43
·期 1
·121-132
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IF 6.15
Zhao Ze-an,Jiang Yu,Chen Yan-yu,Wu Ting,Lan Qun-sheng,Li Yong-mei,Li Lu,Yang Yang,Lin Cui-ting,Cao Ying,Zhou Ping-zheng,Guo Jia-yin,Tian Yuan-xin,Pang Jian-xin
Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo. We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9: CDER167 concentration-dependently inhibited the uptake of [ 14 C]-uric acid in URAT1-expressing HEK293 cells with an IC 50 value of 2.08 ± 0.31 μM, which was similar to that of RDEA3170 (its IC 50 value was 1.47 ± 0.23 μM). Using site-directed mutagenesis, we demonstrated that CDER167 might interact with URAT1 at S35 and F365. In GLUT9-expressing HEK293T cells, CDER167 concentration-dependently inhibited GLUT9 with an IC 50 value of 91.55 ± 15.28 μM, whereas RDEA3170 at 100 μM had no effect on GLUT9. In potassium oxonate-induced hyperuricemic mice, oral administration of CDER167 (10 mg·kg −1 · d −1 ) for 7 days was more effective in lowering uric acid in blood and significantly promoted uric acid excretion in urine as compared with RDEA3170 (20 mg·kg −1 · d −1 ) administered. The animal experiment proved the safety of CDER167. In addition, CDER167 displayed better bioavailability than RDEA3170, better metabolic stability and no hERG toxicity at 100 μM. These results suggest that CDER167 deserves further investigation as a candidate antihyperuricemic drug targeting URAT1 and GLUT9.
研究领域:
药理学
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医学
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药物开发
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PubMed
高影响因子
Foods
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2025
·Vol. 14
·期 16
·2765
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IF 5.1
Furong Xue,Renqin Zhu,Jiaxing Li,Zheng Liu,Lidan Niu,Wei Chen,Chengtao Wang,Jie Zheng
The increasing global prevalence of hyperuricemia (HUA), particularly among younger populations, underscores the urgent need for safe and effective dietary interventions.Monascusfungi, long utilized in East Asian food culture, ferment rice to produce red yeast rice (RYR), a functional food rich in monacolin K and Monascus pigments. Among these,Monascusyellow pigments (MYPs)—natural azaphilone compounds used as food additives and colorants—have shown antioxidant, anti-inflammatory, and metabolic regulatory activities. However, their potential to alleviate hyperuricemia remains unexplored. This study investigates the urate-lowering and organ-protective effects of MYPs through a combination of in vitro, in vivo, and gut microbiota analyses. MYPs exhibited significant xanthine oxidase (XOD) inhibitory activity, and molecular docking confirmed that monascin (MS) and ankaflavin (AK) competitively bind to the XOD active site. In a murine HUA model, MYPs significantly reduced serum uric acid (SUA) levels without causing hepatic or renal toxicity. Mechanistically, MYPs downregulated renal UA reabsorption transporters (URAT1, GLUT9) and upregulated the excretory transporter ABCG2, enhancing uric acid (UA) excretion. These findings highlight MYPs as promising food-derived bioactives with dual XOD inhibition and uricosuric effects, offering a novel nutraceutical strategy for hyperuricemia prevention and management.
研究领域:
食品科学
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生物化学
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药理学
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营养学
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分子生物学
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微生物学
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DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2023
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IF 5.1
Zean Zhao,Jian Luo,Hui Liao,Fengxin Zheng,Xinhua Chen,Jiajun Luo,Yongjun Chen,Kunlu Zhao,Shuqin Zhang,Jinhong Tian,Ting Wu,Yongmei Li,Lu Li,Yang Yang,Cuiting Lin,Qun Zhang,Yuanxin Tian,Jianxin Pang
Previously we discovered a novel natural scaffold compound, isobavachin (4′, 7-dihydroxy-8-prenylflavanone), as a potent URAT1 inhibitor by shape and structure based on a virtue screening approach. In this study, further urate-lowering mechanism, pharmacokinetics and toxicities of isobavachin were conducted. Isobavachin inhibited URAT1 with an IC 50 value of 0.24 ± 0.06 μM, and residues S35, F365, I481 and R477 of URAT1 contributed to high affinity for isobavachin. Isobavachin also inhibited glucose transporter 9 (GLUT9), another pivotal urate reabsorption transporter, with an IC 50 value of 1.12 ± 0.26 μM. Molecular docking and MMGBSA results indicated that isobavachin might compete residues R171, L75 and N333 with uric acid, which leads to inhibition of uric acid transport of GLUT9. Isobavachin weakly inhibited urate secretion transporters OAT1 with an IC 50 value of 4.38 ± 1.27 μM, OAT3 with an IC 50 of 3.64 ± 0.62 μM, and ABCG2 with an IC 50 of 10.45 ± 2.17 μM. Isobavachin also inhibited xanthine oxidase (XOD) activity in vitro with an IC 50 value of 14.43 ± 3.56 μM, and inhibited the hepatic XOD activities at 5–20 mg/kg in vivo . Docking and MMGBSA analysis indicated that isobavachin might bind to the Mo-Pt catalyze center of XOD, which leads to inhibition of uric acid production. In vivo , isobavachin exhibited powerful urate-lowering and uricosuric effects at 5–20 mg/kg compared with the positive drugs morin (20 mg/kg) and RDEA3170 (10 mg/kg). Safety assessments revealed that isobavachin was safe and had no obvious toxicities. Isobavachin has little cell toxicity in HK2 cells as indicated by the MTT assay. In vivo, after treatment with 50 mg/kg isobavachin for 14 days, isobavachin had little renal toxicity, as revealed by serum CR/BUN levels, and no hepatotoxicity as revealed by ALT/AST levels. Further HE examination also suggests that isobavachin has no obvious kidney/liver damage. A pharmacokinetic study in SD rats indicated isobavachin had lower bioavailability (12.84 ± 5.13 %) but long half-time (7.04 ± 2.68 h) to maintain a continuous plasma concentration. Collectively, these results indicate that isobavachin deserves further investigation as a candidate anti-hyperuricemic drug with a novel mechanism of action: selective urate reabsorption inhibitor (URAT1/GLUT9) with a moderate inhibitory effect on XOD.
研究领域:
药理学
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药物化学
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毒理学
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2020
·
IF 3.263
Qiurui Li,Hua Lin,Yanfen Niu,Yan Liu,Zhenyu Wang,Liudong Song,Lihui Gao,Ling Li
Increasing evidence shows that the intestinal tract plays an important role in maintaining urate homeostasis and might be a potential therapeutic target for hyperuricaemia . However, uric acid-lowering drugs available in the clinic do not target intestinal excretion as a therapeutic strategy. We previously reported that mangiferin had potent hypouricaemic effects in hyperuricaemic animals. However, the underlying mechanisms are not completely clear. Here, we investigated the effects of mangiferin on the intestinal excretion of urate and its underlying mechanisms. The data revealed that mangiferin concentration-dependently promoted the intestinal secretion of endogenous urate in in situ intestinal closed loops in normal and hyperuricaemic mice, as well as inhibited the absorption of exogenous uric acid perfused into the intestinal loops in rats. Administration of mangiferin not only decreased the serum urate levels in the hyperuricaemic mice but also increased the protein expression of ATP-binding cassette transporter, subfamily G, member 2 (ABCG2) and inhibited the protein expression of glucose transporter 9 (GLUT 9) in the intestine. These findings suggested that intestinal ABCG2 and GLUT9 might be pivotal and possible action sites for the observed hypouricaemic effects. Moreover, no significant changes in intestinal xanthine oxidoreductase activities were observed, suggesting that mangiferin did not affect intestinal uric acid generation in the hyperuricaemic mice. Overall, promoting intestinal elimination of urate by upregulating ABCG2 expression and downregulating GLUT9 expression might be an important mechanism underlying mangiferin lowering serum uric acid levels. Mangiferin supplementation might be beneficial for the prevention and treatment of hyperuricaemia.
研究领域:
药理学
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生物化学
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医学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2020
·
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
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
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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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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PubMed
高影响因子
危险品化学品经营许可证（带存储）