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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.
Acta Pharmaceutica Sinica ; (12): 1069-1074, 2019.
Article in Chinese | WPRIM | ID: wpr-780183

ABSTRACT

Urate transporter 1 (URAT1) is a validated target for the treatment of hyperuricemia. Based on the structure of URC-102, which is currently under a phase Ⅱ clinical trial, fourteen novel analogs were designed and synthesized. Among them, four compounds (9b, 9c, 10e and 10g) exhibited substantial inhibitory effect against URAT1. The most active compound 9b showed an IC50 value of 0.061 μmol·L-1, which is significantly more potent than Lesinurad and Benzbromarone. Preliminary SAR was drawn, providing clues for further structural optimization.

3.
Acta Pharmaceutica Sinica ; (12): 1387-1396, 2017.
Article in Chinese | WPRIM | ID: wpr-779739

ABSTRACT

Ellipticine is an alkaloid isolated from natural product with cytotoxicity, which has antitumor and anti-aids activity. Since it was first identified in 1959, a great deal of effort has been devoted to the development of various approaches for synthesis of ellipticine. This review provides a summary for synthesis approaches of ellipticine from different starting materials. The antitumor mechanism and structure-activity relationship are also discussed.

4.
Article in Chinese | WPRIM | ID: wpr-232225

ABSTRACT

<p><b>OBJECTIVE</b>To assess the association between single nucleotide polymorphisms (SNPs) of mannose-binding lectin 2 gene (MBL2) (rs1800450, rs1800451 and rs11003125) and protein kinase C-beta 1 gene (PRKC beta 1) (rs3700106, rs2575390) with diabetic macroangiopathy in northern Chinese Han population.</p><p><b>METHODS</b>The samples have included 318 type 2 diabetes mellitus (T2DM) patients and 448 normoglycemic controls. The five SNPs were determined by a Multiplex SnaPshot method. Biochemical indices such as fasting plasma-glucose, triglyceride and total cholesterol were also measured. Linkage disequilibrium and haplotype analysis were carried out for all samples using Haploview 4.2. Additive model was applied to assess the effect of interaction between SNPs and environment factors on macrovascular complications.</p><p><b>RESULTS</b>Genotypic frequencies of rs11003125 have differed significantly between the controls and patients with coronary heart disease and peripheral vascular disease (P=0.024 and 0.004, respectively). The allele frequency of rs11003125 was also statistically significant between the two groups (P=0.014 and 0.001, respectively). Compared with patients without macrovascular complications, the allele frequency of rs11003125 was significantly different in patients with peripheral vascular disease (P=0.031). No significant differences were found between the distribution of the genotype frequency and allele frequencies of other variants. Haplotype analysis indicated that, compared with controls and patients without macrovascular complications, individuals with G allele of rs1800450 and C allele of rs11003125 had a higher risk for macrovascular complications.</p><p><b>CONCLUSION</b>The rs11003125 polymorphism located in the promoter region of MBL2 gene is associated with macrovascular complications of T2DM in northern Chinese Han population. G allele of rs1800450 and C allele of rs11003125 may be risk factors for macrovascular complications. There were additive interactive effects for rs11003125 polymorphism (GC+CC) and hypertension, diabetic nephropathy, diabetic neuropathy and diabetic retinopathy on macrovascular complications.</p>


Subject(s)
Alleles , China , Ethnology , Diabetes Mellitus, Type 2 , Ethnology , Genetics , Diabetic Angiopathies , Ethnology , Genetics , Gene Frequency , Genetic Predisposition to Disease , Genotype , Humans , Mannose-Binding Lectin , Genetics , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Protein Kinase C , Genetics , Protein Kinase C beta
5.
Article in Chinese | WPRIM | ID: wpr-840420

ABSTRACT

Objective:To repair knee joint defects in rabbits with rat adipose-derived stem cells induced by cartilage-derived morphogenetic protein growth factor 1 (CDMP1) ,so as to assess the feasibility of using heterogeneity cells as the seed cells for cartilage tissue engineering. Methods: The second generation ADSCs were seeded on scaffold, cultured for another two weeks in presence of CDMP1(50 μg/L),and identified by immunohistochemistory method. Bilateral rabbit knee joint defect model was established. The left side defect was embedded with ADSCs-scaffold composite (experimental group); the right side was embedded only with the scaffold(control group). Nine rabbits were killed in each group 8,16,24, and 48 weeks after embedding and the tissues were made into slices for safranine O and haematoxylin eosin staining. Results: In the experimental group the defects were filled with white semi-transparent tissues 8 weeks after embedding, with clear boundary to the surrounding cartilage; 16 weeks after embedding, the boundary of defect was further improved but still could be seen; 24 weeks after embedding, the repair outcomes were satisfactory, with the newly-generated chondrocytes having a nearly normal morphology (sphere shape,cartilage lacuna),and safranine O and haematoxylin eosin staining results were both positive; and 48 weeks after embedding, the boundary of the repair region could be clearly seen,and the repair effects were not as satisfactory as those of after 24 weeks. In the control group the boundary between the repairing area and the normal circumjacent area was visible at all 4 time points,with clear boundary and granulation tissues; the newly generated cells took a spindle shape and were negative for H-E and safranine O staining. Conclusion: The knee joint defects of rabbits can be satisfactorily repaired by using CDMP1-induced ADSCs seeded on spongy bone scaffold of cattle, which provides a theoretical basis for using heterogeneity cells as the seed cells for cartilage tissue engineering.

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