Pharmaceuticals
·
2026
·Vol. 19
·期 8
·1261
·
IF 5.7
Yongxin Sun,Hao Tan,Jingyu Zhang,Zengyu Zhang,Shuang Huai,Manli Wang
Background:Hyperuricemia is a well-established risk factor for both chronic kidney disease and gout. Currently available urate-lowering drugs, however, are frequently compromised by hepatorenal toxicity and gastrointestinal adverse effects. Cinnamaldehyde, the principal bioactive constituent of the traditional Chinese medicine cinnamon, has documented renoprotective properties, yet its integrated effects on hyperuricemia-associated renal injury remain incompletely defined.Objectives:This study investigated the therapeutic effects of cinnamaldehyde on hyperuricemia and explored the molecular mechanisms involved.Materials and Methods:An in vivo hyperuricemia model was established in KM mice by co-administration of potassium oxonate and hypoxanthine for 14 consecutive days, and an in vitro injury model was generated by exposing HK-2 human renal tubular epithelial cells to uric acid. For the in vivo study, mice were divided into five groups (control, model, febuxostat, low-dose CA, and high-dose CA;n= 9 per group) and were treated by oral gavage. Serum biochemical indices, renal and intestinal histopathology, inflammatory cytokines, renal urate transporter proteins (OAT1, OCT2, ABCG2, and SLC2A9), and components related to AIF1 and CMPK2/NLRP3 inflammasome signaling (ASC, caspase-1, IL-18, and IL-1β) were examined. Western blotting, qPCR, immunofluorescence, apoptosis analysis, mitochondrial membrane potential assessment, transmission electron microscopy, siRNA-mediated knockdown, and 16S rRNA gene sequencing were used to characterize the relevant mechanisms.Results:CA reduced serum uric acid (p≤ 0.001 vs. model), creatinine (p≤ 0.01 vs. model), and blood urea nitrogen (p≤ 0.01 vs. model), alleviated renal and intestinal histopathological injury, and decreased circulating and renal inflammatory cytokines. Cinnamaldehyde increased ABCG2, OAT1, and OCT2 protein expression and reduced SLC2A9 expression (allp≤ 0.05 vs. model). In vivo and in vitro, cinnamaldehyde suppressed AIF1- and CMPK2/NLRP3-related inflammatory proteins, reduced uric acid-induced apoptosis, and preserved mitochondrial membrane potential and ultrastructure. Fecal 16S rRNA sequencing suggested changes in selected microbial taxa, although alpha-diversity and BrayCurtis-based PERMANOVA/ANOSIM analyses did not demonstrate significant global community separation.Conclusions:These findings suggest that CA alleviates hyperuricemia-associated renal injury by regulating renal urate transporters, attenuating AIF1- and CMPK2/NLRP3-related inflammatory signaling, accompanied by compositional shifts in selected gut microbial taxa that warrant further mechanistic investigation. The study provides experimental support for further evaluation of cinnamaldehyde as a multi-target candidate for hyperuricemia-related renal injury.
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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.
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2021
·
IF 6.953
Yan Liu,Chenggang Han,Tao Lu,Yi Liu,Hao Chen,Can Yang,Yanbei Tu,Yanfang Li
Xanthine oxidase (XO) plays a vital role in inducing hyperuricemia and increasing the level of superoxide free radicals in blood, and is proved as an important target for gout. Chrysoeriol (CHE) is a natural flavone with potent XO inhibitory activity (IC 50 = 2.487 ± 0.213 μM), however, the mechanism of interaction is still unclear. Therefore, a comprehensive analysis of the interaction between CHE and XO was accomplished by enzyme kinetics , isothermal titration calorimetry (ITC), multi-spectroscopic methods, molecular simulation and ADMET. The results showed that CHE acted as a rapid reversible and competitive-type XO inhibitor and its binding to XO was driven by hydrogen bonding and hydrophobic interaction. Moreover, CHE exhibited a strong fluorescence quenching effect through a static quenching procedure and induced conformational changes of XO. Its binding pattern with XO was revealed by docking study and the binding affinity to XO was enhanced by the interactions with key amino acid residues in the active pocket of XO. Further, CHE showed good stability and pharmacokinetic behavior properties in molecule dynamic simulation and ADMET prediction. Overall, this study shed some light on the mechanism of interaction between CHE and XO, also provided some valuable information concerning the future therapeutic application of CHE as natural XO inhibitor.
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高影响因子
ANALYTICAL CHEMISTRY
·
2025
·
IF 6.7
Shuxian Zhang,Xiaofei Wang,Jili Han,Xiaoxuan Fan,Keshuai Liu,Lingling Yang,Hao Yang,Xiaofei Chen,Xueqin Ma,Guoning Chen
Biological aggregates play a crucial role in the pathogenesis of thrombotic diseases, especially thrombin-induced biological aggregates. Therefore, the efficient discovery of thrombin inhibitors is of great significance for the prevention and treatment of thrombotic diseases. In this study, the aggregation precursor protein fluorescent probe was successfully prepared for monitoring the production of biological aggregates induced by thrombin. In this program, the aggregation degree of biomolecules can be quickly monitored through a fluorescence sensing technology. To facilitate the modulation of the biological aggregation process, the application of this advanced fluorescence sensing technology was utilized for the screening of thrombin inhibitors, which are pivotal regulatory molecules in biological aggregation. In addition, by combining the target fishing technique, an integrated model for rapid screening of potential inhibitors in complex extracts was further established. This model not only swiftly detects the presence of inhibitory components within complex systems but also precisely captures and identifies active monomers. After positive drug validation of the screening model, three active monomers, namely, ginkgetin, isoginkgetin, and bilobetin, were accurately screened from 30 natural products. These results highlighted the immense potential of the proposed approach for screening active ingredients from a wide range of natural products.
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高影响因子
BIOORGANIC CHEMISTRY
·
2025
·
IF 4.7
Can Yang,Haiqi Xu,Puchen Zhao,Qin Yin,Na Wang,Lizi Li,Yan Liu,Yanfang Li
2′,4′-dimethoxy-4-hydroxychalcone ( 15b ) has been previously reported as a reversible competitive inhibitor of xanthine oxidase (XOD) with potent activity (> 10-fold vs. allopurinol), but its molecular interactions with the enzyme active site remain uncharacterized. In this research, an integrated approach consisting of multiple spectroscopic methods, isothermal titration calorimetry (ITC), and computer simulations was employed to investigate the binding mode of 15b on XOD. Consequently, ITC data confirmed that the stable 15b -XOD complex was formed spontaneously and driven mainly by hydrophobic interactions with the dissociation constant of the magnitude of 10 −7 mol·L −1 . Three-dimensional fluorescence and circular dichroism spectroscopy indicated that 15b binding induced a conformational transition in the XOD backbone , leading to an increase in global flexibility characterized by enhanced random coil and reduced α-helix/β-sheet. Synchronous fluorescence analysis demonstrated that 15b preferentially perturbed the microenvironment of tyrosine residues over tryptophan residues in XOD. Molecular docking studies (PDB: 1N5X , 2.5 Å) revealed that 15b occupied the xanthine access channel near the molybdenum-pterin (Mo-pt) center, forming critical hydrogen bonds with Arg880 and Thr1010. This binding sterically obstructed substrate xanthine access and subsequent uric acid production. Molecular dynamics simulations indicated that 15b formed a stable binding complex with XOD. Notably, 15b likely bound at the dimer interface and induced inter-subunit proximity, whereas 15b binding preserved the integrity of the surface polarity topology. Furthermore, 15b showed no cytotoxicity in AML-12 hepatocytes at 20 μmol·L −1 (cell viability >90 %) , while suppressing uric acid production (> 40 % reduction at 20 μmol·L − 1 ) . These findings may enrich the interaction mechanism of 15b with XOD and also provide a theoretical basis for ligand-guided design of future novel XOD inhibitors.
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