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1.
Acta Pharmaceutica Sinica ; (12): 1621-1626, 2021.
Article in Chinese | WPRIM | ID: wpr-881566

ABSTRACT

Hyperuricemia is not only the biochemical basis of gout, but also closely related to the development of metabolic syndrome, cardiovascular diseases, chronic kidney disease, etc. Xanthine oxidase (XOD) is the key catalytic enzyme for uric acid biosynthesis, therefore the vital target for anti-hyperuricemic drugs. In this study, compound CC18022 was designed and synthesized specifically targeting to XOD. Molecular docking analysis indicated a fairly tight binding between CC18022 and XOD. In the in vitro study, CC18022 significantly inhibited XOD activity with a half maximal inhibitory concentration (IC50) value in the order of nmol·L-1, which is relative to the XOD inhibitor febuxostat. By using both acute and chronic hyperuricemic mice model, compound CC18022 was found to have serum uric acid-lowering effect in a dose-dependent manner in vivo. The animal welfare and experimental processes were in accordance with the provisions of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences. In the acute hyperuricemic mice, CC18022 significantly inhibited serum XOD activity, and also the XOD activity in intestine and liver, which were related to purine absorption and metabolism. Therefore, the novel compound CC18022 exhibited significant inhibition on XOD activity and anti-hyperuricemic effects, making it a favorable candidate for further research.

2.
Chinese Pharmacological Bulletin ; (12): 1471-1477, 2019.
Article in Chinese | WPRIM | ID: wpr-857137

ABSTRACT

Aim To establish a screening system for xanthine oxidase (XOD) inhibitors. Methods The XOD activity in vitro, serum uric acid level, serum XOD activity, tissue XOD activity and the blood indexes related to liver and kidney function were determined by biochemical method, respectively. Pathological analysis was used to observe liver and kidney. Results The optimized reaction consists of 3 U . L 1 XOD and 50 u,mol . L 1 XA under pH7.4, 37 °C. for 20 min. The high throughput screening method was established for XOD inhibitors in vitro. The acute hyperuricemia models were induced by signle dose of hypoxanthine and oteracil potassium in ICR mice. In this case, the serum uric acid level had a transient elevation after inducer administered. The changes of serum uric acid levels and the area under the uric acid-time curve were used to evaluate the acute hyperuricemia mice. The chronic hyperuricemia models were selected from the ICR mice stimulated with oteracil potassium consecutively. No significant changes of XOD activities in serum and tissue, of function and pathological structure in liver and kidney were observed in both acute hyperuricemia mice and chronic hyperuricemia mice. Conclusions The high throughput screening method for XOD inhibitors in vitro and the evaluation in vivo, in acute or chronic hyperuricemia mice, respectively, are mutually verified, forming an experimental system for developing the anti-hyperuricemia drug targeting at XOD.

3.
Chinese Journal of Neuromedicine ; (12): 475-479, 2011.
Article in Chinese | WPRIM | ID: wpr-1033267

ABSTRACT

Objective To explore the protective effect of insulin-like growth factor 1 (IGF-1) on apoptosis of dopaminergic neurons induced by L-dopa via JAK/STAT signaling pathway. Methods PC12 cells were induced to differentiate into dopaminergic neurons with 100 μg/L β-NGF; MTT assay was employed to identify the changes in the viability of PC12 cells following L-dopa treatment at 0, 10,20, 50, 100, 150 and 200 μmol/L, and the different concentrations of IGF-1 at 0, 10, 25, 50 and 100 nmol/L with the same concentration of L-dopa (150 μmol/L); Western blotting was used to detect the levels of P-JAK2/P-STAT3 in PC12 cells treated with PBS (controls), L-dopa, L-dopa+IGF-1 and L-dopa+IGF-1+AG490 for 24 h, and then the apoptosis rate was assessed by flow cytometry and Hchest33258 staining. Results Western blotting showed that the expressions of P-JAK2 and P-STAT3 were detected in the L-dopa+IGF-1 and L-dopa+IGF-1+AG490 treatment groups but not in the control group or L-dopa treatment group; the expression of P-STAT3 in the L-dopa+IGF-1+AG490 treatment group was obviously lower than that in the L-dopa+IGF-1 treatment group (P<0.05). Hchest33258 staining indicated that L-dopa treatment group had the most obvious karyopyknosis and karyorrhexis,much more apoptotic bodies than the L-dopa+IGF-1 and L-dopa+IGF-1+AG490 treatment groups. Flow cytometry showed that the apoptosis rate was significantly different among the 4 groups (F=180.991,P=0.000): as compared with the control group, the other 3 groups had a higher apoptosis rate (P<0.05);L-dopa treatment group (38.13 ±2.54 %) enjoyed the highest level, followed by L-dopa+IGF-1 +AG490treatment group (25.60±1.30 %) and L-dopa+IGF-1 treatment group (20.17±1.54 %). Conclusion L-dopa has toxic effect on PC12 cells; IGF-1 could protect the PC12 cells from the neurotoxic effect of L-dopa and JAK2/STAT3 signaling pathway is activated in this procedure.

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