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@#Thioredoxin-interacting protein (TXNIP), which mainly regulates glucose homeostasis in pancreatic β cells, is a novel target in the treatment of diabetes.In this study, 4-hydroxybenzopyrimidine was used as the raw material, four nitrogen-containing rings (imidazole, methylpiperazine, pyrazole, morpholine) were introduced, benzopyrimidine skeleton with nitrogen-containing rings derivatives targeting TXNIP was designed and synthesized, and the protective effect of compounds on palmitic acid-stimulated islet β cells was investigated.A total of 20 benzopyrimidine derivatives were designed and synthesized, and the structures were confirmed by 1H NMR and ESI-MS.Pharmacological studies showed that most of the compounds exhibited protective effects on islet β cells, with better axtivity for compounds C-1, C-2, C-4 and D-2 (cell survival rate > 70%) compared with PA model group (38.3%), Among the four compounds, D-2 had the highest activity of 87.2%, so it could become a potential new anti-diabetic chemical entity.
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Thioredoxin⁃interacting protein (TXNIP), also known as vitamin D3 up⁃regulation protein 1, is named for its ability to bind to thioredoxin (TRX) and inhibit its activity and expression. This article summarizes the discovery and structure of TXNIP, and its effect on the development of prediabetes by regulating the metabolism of glucose and lipid. On this basis, two main pathways of TXNIP participating in the development of diabetes are summarized: TXNIP induces apoptosis of islet cells by antagonizing the anti⁃apoptosis effect of TRX; Over⁃expression of TXNIP promotes the phosphorylation of islet cells and increases the expression of tumor suppressor⁃related protein, which leads to the senescence of islet cells. The role of TXNIP in diabetic complications such as diabetic cardiomyopathy, diabetic diabetic nephropathy and diabetic retinopathy is emphasized. TXNIP can further participate in physiological and biochemical processes such as oxidative stress, autophagy, apoptosis, glucose and lipid metabolism and activation of inflammation through various indirect pathways. Therefore, it is important to understand the mechanism of TXNIP in diabetes mellitus and its complications. Finally, the potential application of TXNIP in diabetes was discussed. Methylation of single TXNIP gene cannot fully reveal the molecular mechanism of diabetes and its complications. In the future, we can study how TXNIP gene interacts with other genes or risk factors, and participates in the occurrence and development of diabetes and its complications. These in⁃depth studies will lay a foundation for the application of target molecules in the diagnosis and treatment of diabetes and its complications.
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OBJECTIVE: To study the effect of curcumin on the oxidative stress induced by nano-silicon dioxide( SiO_2) in A549 cells and to explore its potential mechanism. METHODS: A549 cells were randomly divided into 6 groups. Nano-SiO_2 group cells were stimulated with nano-SiO_2 solution with a final concentration of 20 mg/L; curcumin low-,medium-,and high-dose group cells were treated with curcumin at final concentrations of 5,10,and 20 μmol/L respectively and 20 mg/L nano-SiO_2 solution; the solvent control group was treated with dimethyl sulfoxide with a volume fraction of 0. 10%. The cells in the blank control group were not given any treatment. The cells in these 6 groups were incubated for 12 hours,and the level of malondialdehyde( MDA) and the activity of total superoxide dismutase( T-SOD) in the cells were measured by spectrophotometer. The relative expression of mRNA and protein of nuclear factor E2-associated factor 2( NRF2),thioredoxin-1( TRX1),and thioredoxin interaction protein( TXNIP) were analyzed by real-time fluorescent quantitative polymerase chain reaction and Western blot respectively. RESULTS: The MDA level in A549 cells of nano-SiO_2 group increased( P < 0. 05),the T-SOD activity decreased( P < 0. 05),and the mRNA and protein relative expression of NRF2 and TRX1 were up-regulated( P < 0. 05),TXNIP relative expression of mRNA and protein were down-regulated( P <0. 05),when compared with the blank control group and the solvent control group. After intervention with curcumin,with the increased of curcumin concentration,the MDA level in A549 cells decreased,the T-SOD activity increased,the relative expression of NRF2 mRNA and TRX1 mRNA and protein was up-regulated,the mRNA and protein relative expression of TXNIP was down-regulated,and showed a dose-dependent manner( P < 0. 01). CONCLUSION: Curcumin can protect nano-SiO_2-induced oxidative stress in A549 cells. It may activate TRX system by regulating NRF2/antioxidant response elements pathway,exerting an anti-oxidation effect and protecting cells from excessive oxidative damage.
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Objective To investigate the effect of TXNIP in renal ischemia-reperfusion injury induced apoptosis in human kidney proximal tubular cell line. Methods To build an injury model of HK-2 cells in vitro. The level of ROS and rate of apoptosis were analyzed by flow cytometry. The expression levels of proteins were observed by Western Blot. The expression level of TXNIP mRNA was observed by RT-qPCR. Results Compared with the control group,the level of ROS,the rate of cell apoptosis,the expression of cleaved caspase-3 significantly increased(P<0.01),and the expression of GPX4 significantly decreased in HK-2 cells in the OGD/R group(P<0.01).Compared with the OGD/R group,the expression of TXNIP protein and mRNA significantly decreased(P<0.01),the level of ROS,the rate of cell apoptosis significantly decreased(P<0.01),and the expression of GPX4 significantly increased in HK-2 cells in the siRNA TXNIP group(P < 0.01). Conclusion Down regulation of TXNIP can inhibit IRI-induced HK-2 apoptosis through activating GPX4 and decreasing ROS.