JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE
·
2025
·
IF 3.5
Jianmei Sun,Zhouyang Shen,Yuling Sun,Ye You,Chan Zhu,Shuo Cheng,Guang Yu,Yan Yang,Zongxiang Tang
BACKGROUND Cinnamic acid derivatives, such as p -coumaric acid, caffeic acid, ferulic acid, and chlorogenic acid, exhibit uric acid-lowering effects through the inhibition of xanthine oxidase (XOD). While the clinically used XOD inhibitor allopurinol is associated with significant side effects, these natural polyphenolic compounds exhibit comparable efficacy with improved safety. RESULTS In hyperuricemic mouse models and in vitro assays, these polyphenolic compounds effectively reduced serum uric acid levels through XOD inhibition. Notably, ferulic acid and caffeic acids exhibited superior potency and reduced hepatic and renal toxicity in comparison to p -coumaric acid, with molecular docking studies suggesting competitive binding at the active site of XOD. Additionally, chlorogenic acid demonstrated significant activity. CONCLUSION These findings underscore the potential of naturally derived polyphenolics as promising candidates for the management of hyperuricemia, providing a safer alternative to conventional therapies. © 2025 Society of Chemical Industry.
研究领域:
药理学
·
代谢疾病研究
·
天然产物化学
✓ 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
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
·
2022
·
IF 7.088
Wen Peng,Fuyao Liu,Lei Zhang,Liying Zhang,Jing Li
Based on analyses of the interaction between febuxostat and xanthine oxidoreductase (XOR), tetrazole was used to replace the carboxyl-thiazole fragment of febuxostat using a bioelectronic isosteric strategy. Three series of compounds were designed. The inhibitory activity against XOR of all compounds was evaluated and their structure–activity relationships determined. The inhibitory activity against XOR of compounds I was weak, with a half-maximal inhibitory concentration (IC 50 ) value > 10 μmol, whereas the inhibitory activity of compounds II and III was increased significantly, among which compounds IIIa (IC 50 = 26.3 ± 1.21 nM) and IIIc (IC 50 = 29.3 ± 0.88 nM) were the best. Molecular docking showed that tetrazole could enter the active cavity instead of a carboxyl group and retain most of the interaction between febuxostat and XOR. For compounds III , the hydrogen bonds with Asn768 and Thr1010 of XOR were absent, but some new interactions were introduced to improve potency. A potassium oxazinate/hypoxanthine-induced model of acute hyperuricemia in mice also showed a significant hypouricemia effect of compounds IIIa , IIIc , and IIIe ( P < 0.01), which was consistent with the results of inhibition in vitro . In conclusion, we identified a promising XOR inhibitor and provided new ideas for the design of XOR inhibitors.
研究领域:
药物化学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
·
2021
·
IF 3.503
Danling Liang,Tianqiao Yong,Xue Diao,Shaodan Chen,Diling Chen,Chun Xiao,Dan Zuo,Yizhen Xie,Xinxin Zhou,Huiping Hu
Context Poria coco F.A.Wolf (Polyporaceae) dispels dampness and promotes diuresis implying hypouricaemic action.Objective To examine hypouricaemic action of Poria coco.Materials and methods Ethanol extract (PCE) was prepared by extracting the sclerotium of P. cocos with ethanol, and the water extract (PCW) was produced by bathing the remains with water. PCE and PCW (50, 100 and 200 mg/kg, respectively) were orally administered to hyperuricemic Kunming mice (n = 8) to examine its hypouricaemic effect. Also, molecular docking was performed.Results P. cocos showed excellent hypouricaemic action, decreasing the serum uric acid of hyperuricaemia (HUA) control (526 ± 112 μmol/L) to 178 ± 53, 153 ± 57 and 151 ± 62 μmol/L (p < 0.01) by PCE and 69 ± 23, 63 ± 15 and 62 ± 20 μmol/L (p < 0.01) by PCW, respectively. According to SCrs, BUNs and H&E staining, PCE and PCW partially attenuated renal dysfunction caused by HUA. They presented no negative effects on ALT, AST and ALP activities. They elevated ABCG2 (ATP-binding cassette super-family G member 2) mRNA and protein expression in comparison to HUA control. In molecular docking, compound 267, 277, 13824, 15730 and 5759 were predicted as the top bioactives of P. cocos against HUA, which even presented better scores than the positive compound, oestrone 3-sulfate.Discussion and conclusions This paper demonstrated the hypouricaemic and nephroprotective effects of P. cocos in hyperuricemic mice by up-regulating ABCG2. These results may be useful for the development of a hypouricaemic agent.
研究领域:
药理学
·
分子生物学
·
中医
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF FOOD BIOCHEMISTRY
·
2021
·Vol. 45
·期 8
·e13856
·
IF 2.72
Liyan Yuan,Zhijie Bao,Tiecheng Ma,Songyi Lin
The hypouricemic effect of corn silk flavonoids (CSFs) in vivo that were extracted by ethanol and fractionated by continuous elution with 40% (CSF-A) and 60% (CSF-B) ethanol solutions on polyamide column were investigated in this study. CSFs reduced serum uric acid (UA) level in a mouse model of potassium oxonate-induced hyperuricemia. CSF-B had the best hypouricemic effect, as it decreased the serum UA level by 26.69% and xanthine oxidase (XO) activity in the serum by 11.29%. The mechanism of action of CSF-B was related to the inhibition of XO activity and the promotion of UA excretion. CSF-B was found to contain 12 kinds of major flavonoids, five of which were speculated to influence its activity in the hyperuricemia mice. The five flavonoids were apigenin-6-C-glucoside-7-O-glucoside, kaempferol-3-O-rutinoside, luteolin-7-glucoside, luteolin-3′,7-di-O-glucoside, and naringenin, respectively. Structure analysis revealed that C-4′, C5 hydroxyl groups, and C2=C3 double bonds in CSF-B gave the latter its hypouricemic effect. Practical applications The prevalence of hyperuricemia has increased in recent times. Current hypouricemic drugs have side effects and can easily lead to various complications. Therefore, it is of great practical significance to find safer and more effective hypouricemic drugs. This study demonstrated that corn silk flavonoids may be used as a dietary supplement to manage hyperuricemia.
研究领域:
药理学
·
生物化学
·
营养学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Jiana Du,Na Wang,Dehong Yu,Pei He,Yu Gao,Yanbei Tu,Yanfang Li
Background : Hyperuricemia (HUA) is a metabolic disease characterized by a high level of uric acid (UA). The extensive historical application of traditional Chinese medicine (TCM) offers a range of herbs and prescriptions used for the treatment of HUA-related disorders. However, the core herbs in the prescriptions and their mechanisms have not been sufficiently explained. Purpose : Our current investigation aimed to estimate the anti-HUA effect and mechanisms of Paeonia veitchii Lynch, an herb with high use frequency identified from data mining of TCM prescriptions. Methods : Prescriptions for HUA/gout treatment were statistically analyzed through a data mining approach to determine the common nature and use frequency of their composition herbs. The chemical constituents of Paeonia veitchii extract (PVE) were analyzed by UPLC-QTOF-MS/MS, while its UA-lowering effect was further evaluated in adenosine-induced liver cells and potassium oxonate (PO) and hypoxanthine (HX)-induced HUA mice. Results : A total of 225 prescriptions involving 246 herbs were sorted out. The properties, flavors and meridians of the appearing herbs were mainly cold, bitter and liver, respectively, while their efficacy was primarily concentrated on clearing heat and dispelling wind. Further usage frequency analysis yielded the top 20 most commonly used herbs, in which PVE presented significant inhibitory activity (IC 50 = 131.33 µg/mL) against xanthine oxidase (XOD), and its constituents showed strong binding with XOD in a molecular docking study and further were experimentally validated through XOD enzymatic inhibition and surface plasmon resonance (SPR). PVE (50 to 200 μg/mL) dose-dependently decreased UA levels by inhibiting XOD expression and activity in BRL 3A liver cells. In HUA mice, oral administration of PVE exhibited a significant UA-lowering effect, which was attributed to the reduction of UA production by inhibiting XOD activity and expression, as well as the enhancement of UA excretion by regulating renal urate transporters (URAT1, GLUT9, OAT1 and ABCG2). Noticeably, all doses of PVE treatment did not cause any liver injury, and displayed a renal protective effect. Conclusions : Our results first comprehensively clarified the therapeutic effect and mechanisms of PVE against HUA through suppressing UA production and promoting UA excretion with hepatic and renal protection, suggesting that PVE could be a promising UA-lowering candidate with a desirable safety profile for the treatment of HUA and prevention of gout.
研究领域:
药理学
·
传统中药
·
代谢性疾病
·
分子生物学
·
数据挖掘
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6
Zean Zhao,Xinhua Chen,Jiajun Luo,Mengyu Chen,Jian Luo,Jianjun Chen,Zhonghuang Li,Shanhe Wan,Ting Wu,Jiajie Zhang,Jianxin Pang,Yuanxin Tian
Previously, we reported a novel natural scaffold compound, isobavachin (4′,7-dihydroxy-8-prenylflavanone), as a highly potent hURAT1 inhibitor with anti-hyperuricemia effect. However, the structure-activity relationship remains unknown and the poor pharmacokinetic (PK) parameters may limit further clinical use. Herein, a series of isobavachin derivatives were rationally designed and synthesized to explore the structure-activity relationship of isobavachin target hURAT1, and to improve their PK properties. Among them, compounds 15d, 15f, 15g, 27b and 27d showed promising hURAT1 inhibitory activities, which could comparable to that of isobavachin (IC 50 = 0.24 μM). In addition, 27b also inhibited another urate reabsorption transporter GLUT9 with an IC 50 of 4.47 μM. Compound 27b displayed greater urate-lowering activity in a hyperuricemia mouse model at a dose of 10 mg/kg compared to isobavachin and lesinurad. Overall, our results suggest that compound 27b represents a novel, safe hURAT1 and GLUT9 dual-target inhibitor with excellent drug availability and is worthy of further investigation as an anti-hyperuricemia agent.
研究领域:
药物化学
·
药理学
·
药物发现
✓ 已验证
产品关联
DOI
PubMed
高影响因子
AMERICAN JOURNAL OF CHINESE MEDICINE
·
2018
·Vol. 46
·期 03
·585-599
·
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
·
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 SEPARATION SCIENCE
·
2024
·Vol. 47
·期 3
·2300741
·
IF 2.8
Zhenqiang Wang,Jinqian Yu,Lei Zhao,Tong Niu,Xiao Wang
In the present study, twelve compounds from Dioscorea spongiosa were successfully purified by an efficient technique combined bioassay-guided fractionation macroporous resin column chromatography (MRCC) pretreatment and high-speed counter-current chromatography (HSCCC) separation for the first time. Then, D101 MRCC was used to fractionate the crude extract into five parts, which further applied the bioassay-guided fractionation strategy to screen the active fractions of 2 and 4. As for the separation, 200 mg Fr.2 was purified by HSCCC using EtOAc/ n -BuOH/H 2 O (2:2:3, v/v), leading to annulatomarin ( 1 ), dioscoresides C ( 2 ), diosniponol C ( 3 ), methyl protodioscin ( 4 ), pseudoprotodioscin ( 5 ), protogracillin ( 6 ), as well as 200 mg Fr.4 yielding montroumarin ( 7 ), dioscorone A ( 8 ), diosniponol D ( 9 ), protodioscin ( 10 ), gracillin ( 11 ), and dioscin ( 12 ) using CH 2 Cl 2 /MeOH/H 2 O (3:3:2, v/v) with the purities over 95.0%. Finally, the isolates were assayed for their anti-inflammatory, urico-lowering, and anti-diabetic activities in vitro, which indicated that the steroidal saponins of 5 , 6 , and 11 showed all these three activities.
研究领域:
生药学
·
天然产物化学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
mSphere
·
2024
·
IF 3.7
Wenxuan Liu,Fulong Nan,Fengjun Liu,Xiaoli Yang,Zonghui Li,Shasha Jiang,Xianjuan Zhang,Jun Li,Meng Yu,Yunyang Wang,Bin Wang
Hyperuricemia has become the second most prevalent metabolic disease after diabetes, but the limitations of urate-lowering treatment (ULT) drugs and patient nonadherence make ULT far less successful. Thus, more ULT approaches urgently need to be explored. Uric acid-degrading bacteria have potential application value in ULT. In this study, we isolated 44XBT, a uric acid-degrading bacterium, from black-headed gull (Chroicocephalus ridibundus) feces. Using a polyphasic taxonomic approach, strain 44XBT was identified as a novel genus within the family Bacillaceae; subsequently, the name Aciduricibacillus chroicocephali was proposed. Strain 44XBT had a unique uric acid-dependent phenotype and utilized uric acid and allantoin as the sole carbon and nitrogen sources, but not common carbon sources or complex media. In the genome, multiple copies of genes involved in uric acid metabolic pathway (pucL, pucM, uraD, and allB) were found. Six copies of pucL (encoding urate oxidase) were detected. Of these, five pucL copies were in a tandem arrangement and shared 70.42%–99.70% amino acid identity. In vivo experiments revealed that 44XBT reduced serum uric acid levels and attenuated kidney damage in hyperuricemic mice through uric acid catalysis in the gut and gut microbiota remodeling. In conclusion, our findings discover a strain for studying bacterial uric acid metabolism and may provide valuable insights into ULT.
研究领域:
微生物学
·
代谢疾病
·
药理学
·
基因组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2016
·Vol. 6
·期 114
·113527-113537
·
IF 3.289
Hongjin Tang,Lin Yang,Wei Li,Jiahuang Li,Jun Chen
Xanthine oxidase (XO) has emerged as an important target not only for gout but also for cardiovascular diseases and metabolic disorders involving hyperuricemia. Salvia miltiorrhiza, a traditional Chinese medicine, is widely used for the clinical treatment of cardiovascular diseases. Herein, an integrated approach consisting of computational analysis and experimental studies was employed to analyze the interaction between S. miltiorrhiza and XO. Molecular docking simulations were performed to reveal the binding characteristics of the chemicals identified in S. miltiorrhiza on the basis of the total docking score and key molecular determinants for binding. The affinities of 10 representative compounds from the herb to XO were predicted and then confirmed by enzyme inhibitory assay in vitro. The binding specificity of these compounds was further validated by enzyme channel blocking, which contributed to elucidating the interaction mechanisms between the herb and XO. Results suggested that several compounds in S. miltiorrhiza exhibited a potential XO inhibitory activity with the molybdenum-pterin center domain as the active binding site. Salvianolic acid C, the active XO inhibitor, also exerted a potent hypouricemic effect on the mouse model induced by potassium oxonate. Such findings may be used to indicate the usefulness of the integrated approach for this scenario.
研究领域:
药理学
·
生物信息学
·
药物化学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）