evp-4593 and Disease-Models--Animal

The pathogenicity of HCC could be enhanced by TNF-α and NFκB, which are crucial parts of the inflammatory pathway inside the HCC microenvironment. Therefore, we aimed to discover the therapeutic effects of QNZ, an inhibitor of both TNF-α and NFκB, in an experimental model of HCC in rats. HCC was experimentally induced in rats by thioacetamide, and some of the rats were treated with QNZ. The expression levels of nuclear factor (NF)κB, tumor necrosis factor (TNF)-α, apoptosis signal regulating kinase (ASK)-1, β-catenin, glycogen synthase kinase (GSK)-3 and TNF receptor-associated factor (TRAF) were examined in hepatic samples. In addition, hepatic tissues were stained with hematoxylin/eosin and anti-TNF-α antibodies. QNZ blocked HCC-induced expression of both NFκB and TNF-α. It significantly reduced both α-fetoprotein and the average number of nodules and increased the survival rate of the HCC rats. Moreover, hematoxylin and eosin liver sections from the HCC rats showed vacuolated cytoplasm and necrotic nodules. All of these effects were alleviated by QNZ treatment. Finally, treating HCC rats with QNZ resulted in a reduction in the expression of TRAF, ASK-1 and β-catenin, as well as increased expression of GSK-3. In conclusion, inhibition of the inflammatory pathway in HCC with QNZ produced therapeutic effects, as indicated by an increased survival rate, reduced serum α-fetoprotein levels, decreased liver nodules and improved the hepatocyte structure. In addition, QNZ significantly reduced the expression of TRAF, ASK-1 and β-catenin that were associated with increased expression of GSK-3.

Topics: alpha-Fetoproteins; Animals; beta Catenin; Carcinoma, Hepatocellular; Disease Models, Animal; Glycogen Synthase Kinase 3; Hepatocytes; Inflammation; Liver; Liver Neoplasms; MAP Kinase Kinase Kinase 5; NF-kappa B; Organ Specificity; Phenyl Ethers; Quinazolines; Rats; Rats, Sprague-Dawley; Survival Analysis; TNF Receptor-Associated Factor 2; Tumor Necrosis Factor-alpha

Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine expansion within Huntingtin (Htt) protein. In the phenotypic screen we identified a class of quinazoline-derived compounds that delayed a progression of a motor phenotype in transgenic Drosophila HD flies. We found that the store-operated calcium (Ca(2+)) entry (SOC) pathway activity is enhanced in neuronal cells expressing mutant Htt and that the identified compounds inhibit SOC pathway in HD neurons. The same compounds exerted neuroprotective effects in glutamate-toxicity assays with YAC128 medium spiny neurons primary cultures. We demonstrated a key role of TRPC1 channels in supporting SOC pathway in HD neurons. We concluded that the TRPC1-mediated neuronal SOC pathway constitutes a novel target for HD treatment and that the identified compounds represent a novel class of therapeutic agents for treatment of HD and possibly other neurodegenerative disorders.

Topics: Animals; Apoptosis; Calcium; Cells, Cultured; Disease Models, Animal; Drosophila; Fura-2; Glutamic Acid; Huntingtin Protein; Huntington Disease; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neurons; NF-kappa B; Nuclear Proteins; Phenyl Ethers; Quinazolines; RNA Interference; RNA, Small Interfering; TRPC Cation Channels