JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
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
·
肾病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
·
IF 4.2
Yongmei Li,Fengxin Zheng,Shiqi Zhong,Kunlu Zhao,Hui Liao,Jiacheng Liang,Qiang Zheng,Huicong Wu,Shifan Zhang,Ying Cao,Ting Wu,Jianxin Pang
Hyperuricemic nephropathy (HN) is characterized by renal fibrosis and tubular necrosis caused by elevated uric acid levels. Ferroptosis, an iron-dependent type of cell death, has been implicated in the pathogenesis of kidney diseases. The objective of this study was to explore the role of ferroptosis in HN and the impact of a ferroptosis inhibitor, ferrostatin-1 (Fer-1). The study combined adenine and potassium oxonate administration to establish a HN model in mice and treated HK-2 cells with uric acid to simulate HN conditions. The effects of Fer-1 on the renal function, fibrosis, and ferroptosis-associated molecules were investigated in HN mice and HK-2 cells treated with uric acid. The HN mice presented with renal dysfunction characterized by elevated tissue iron levels and diminished antioxidant capacity. There was a significant decrease in the mRNA and protein expression levels of SLC7A11, GPX4, FTL-1 and FTH-1 in HN mice. Conversely, treatment with Fer-1 reduced serum uric acid, serum creatinine, and blood urea nitrogen, while increasing uric acid levels in urine. Fer-1 administration also ameliorated renal tubule dilatation and reduced renal collagen deposition. Additionally, Fer-1 also upregulated the expression levels of SLC7A11, GPX4, FTL-1, and FTH-1, decreased malondialdehyde and iron levels, and enhanced glutathione in vivo and in vitro . Furthermore, we first found that Fer-1 exhibited a dose-dependent inhibition of URAT1, with the IC 50 value of 7.37 ± 0.66 μM. Collectively, the current study demonstrated that Fer-1 effectively mitigated HN by suppressing ferroptosis, highlighting the potential of targeting ferroptosis as a therapeutic strategy for HN.
研究领域:
肾病学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2021
·
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
·
肾病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2021
·Vol. 43
·期 1
·121-132
·
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
·
医学
·
药物开发
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
·
2024
·
IF 2.7
Chunying Du,Hua Yin,Aowei Xie,Junhong Yu,Yifan Wang,Fengli Yao,Siyu Zhang,Yidan Zhang,Lu Liu,Peng Wang,Jianjun Dong,Ximing Xu
Hyperuricemia is mainly caused by insufficient renal urate excretion. Urate transporter 1 (URAT1), an organic anion transporter, is the main protein responsible for urate reabsorption. In this study, we utilized artificial intelligence-based AlphaFold2 program to construct URAT1 structural model. After molecular docking and conformational evaluation, four e-pharmacophoric models were constructed based on the complex structures of probenecid-URAT1, benzbromarone-URAT1, lesinurad-URAT1, and verinurad-URAT1. Combining pharmacophore modeling, molecular docking, MM/GBSA calculation and ADME prediction, 25 flavonoids were selected from the natural products database containing 10,968 molecules. Then, a model of HEK-293T cells overexpressing URAT1 was constructed, and the inhibitory activity to URAT1 of 25 flavonoids was evaluated by measuring their effect on cellular uptake of 6-carboxyfluorescein (6-CFL). Fisetin, baicalein, and acacetin showed the best activity with IC50 values of 12.77, 26.71, and 57.30 µM, respectively. Finally, the structure-activity relationship of these three flavonoids was analyzed by molecular docking and molecular dynamics simulations. The results showed that the carbonyl group on C-4 and hydroxyl group on C-7, C-4', and C-5’ in flavonoids were conducive for URAT1 inhibitory effects. This study facilitates the application of flavonoids in the development of URAT1 inhibitors.Communicated by Ramaswamy H. Sarma
研究领域:
药理学
·
生物信息学
·
分子生物学
·
药物发现
✓ 已验证
DOI
PubMed
高影响因子
Foods
·
2025
·Vol. 14
·期 16
·2765
·
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
·
生物化学
·
药理学
·
营养学
·
分子生物学
·
微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2023
·
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
·
药物化学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6
Chao Yang,Haojie Cai,Xinying Zhu,Lei Zhang,Jing Li
Xanthine oxidoreductase (XOR) and uric acid transporter 1 (URAT1) are two most widely studied targets involved in production and reabsorption of uric acid, respectively. Marketed drugs almost target XOR or URAT1, but sometimes, single agents might not achieve aim of lowering uric acid to ideal value in clinic. Thus, therapeutic strategies of combining XOR inhibitors with uricosuric drugs were proposed and implemented. Based on our initial work of virtual screening, A and B were potential hits for dual-targeted inhibitors on XOR/URAT1. By docking A / B with XOR/URAT1 respectively, compounds I1-7 were designed to get different degree of inhibition effect on XOR and URAT1, and I7 showed the best inhibitory effect on XOR (IC 50 = 0.037 ± 0.001 μM) and URAT1 (IC 50 = 546.70 ± 32.60 μM). Further docking research on I7 with XOR/URAT1 led to the design of compounds II with the significantly improved inhibitory activity on XOR and URAT1, such as II11 and II15 . Especially, for II15 , the IC 50 of XOR is 0.006 ± 0.000 μM, superior to that of febuxostat (IC 50 = 0.008 ± 0.000 μM), IC 50 of URAT1 is 12.90 ± 2.30 μM, superior to that of benzbromarone (IC 50 = 27.04 ± 2.55 μM). In acute hyperuricemia mouse model, II15 showed significant uric acid lowering effect. The results suggest that II15 had good inhibitory effect on XOR/URAT1, with the possibility for further investigation in in-vivo models of hyperuricemia.
研究领域:
药理学
·
药物化学
·
药物发现
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
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
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
·
2020
·
IF 3.004
Chen Sun,Mingyu Zhang,Yanhong Zhao,Jianxin Pang,Ying Peng,Jiang Zheng
Urate anion exchanger 1 (URAT1) expressed in the proximal renal tubules is responsible for about 90% of the reabsorption of uric acid. URAT1 is identified as an important target of uricosuric drugs. Here we present an LC-MS/MS-based approach, combined with URAT1-transgenic MDCK cells, for the assessment of uric acid. Cell lysis was executed with 50 mM NaOH to release uric acid. 1,3- 15 N 2 uric acid was employed as the internal standard. The harvested uric acid, along with the stable isotope-labeled uric acid, was analyzed by LC-MS/MS in multiple reactions monitoring and negative modes. Validation, i.e. determination of selectivity, precision, accuracy, extraction recovery, and matrix effect, and feasibility was evaluated by use of the approach developed. The linearity was observed in the range of 1.0–250 μM (r = 0.9960) with limit of detection of 50 nM and limit of quantitation of 200 nM. The precision and accuracy were found to be RSD ≤ 20% and 80–120% of the nominal value, respectively. Uric acid uptake showed concentration and time dependency in URAT1-transgenic cells. The observed inhibitory effects of three URAT1-targeted uricosuric drugs were consistent with those reported in literature. The stable isotope dilution-based approach was proven to be selective, sensitive, and convenient, which is a good in vitro model for URAT1-targeted drug candidate screening.
研究领域:
药理学
·
分析化学
·
医学
✓ 已验证
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
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Microbiology
·
2018
·
IF 4.019
Yong Tianqiao,Chen Shaodan,Xie Yizhen,Chen Diling,Su Jiyan,Shuai Ou,Jiao Chunwei,Zuo Dan
Recently, we've reported the anti-hyperuricemic effects of Cordyceps militaris. As a characteristic compound of C. militaris, we hypothesized that cordycepin may play a role in preventing hyperurecimia. Remarkably, cordycepin produced important anti-hyperuricemic actions, decreasing SUA (serum uric acid) to 216, 210, and 203 μmol/L (P < 0.01) at 15, 30, and 60 mg/kg in comparison of hyperuricemic control (337 μmol/L), closing to normal control (202 μmol/L). Elisa, RT-PCR and western blot analysis demonstrated that the actions may be attributed to its downregulation of uric acid transporter 1 (URAT1) in kidney. Serum creatinine levels and blood urine nitrogen and liver, kidney, and spleen coefficients demonstrated that cordycepin may not impact liver, renal, and spleen functions. In addition, we used computational molecular simulation to investigate the binding mechanism of cordycepin. Of which, van der Waals interaction dominated the binding. Residues TRP290, ARG17, ALA408, GLY411, and MET147 contributed mainly on nonpolar energy. This provided the theoretical guidance to rationally design and synthesis novel URAT1 inhibitors.
研究领域:
药理学
·
生物化学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）