Discovery of novel benzylquinazoline molecules as p97/VCP inhibitors.

Introduction: Protein p97 is an extensively investigated AAA ATPase with various cellular activities, including cell cycle control, ubiquitin-proteasome system, autophagy, and NF-κB activation. Method: In this study, we designed, synthesized and evaluated eight novel DBeQanalogs as potential p97 inhibitors in vivo and in vitro. Results: In the p97 ATPase inhibition assay, compounds 6 and 7 showed higher potency than the known p97 inhibitors, DBeQ and CB-5083. Compounds 4-6 dramatically induced G0/G1 phase arrest in the HCT116 cells, and compound 7 arrested the cells in both G0/G1 and S phases. Western blots showed elevated levels of SQSTM/p62, ATF-4, and NF-κB in HCT116 cells with the treatment of compounds 4-7, confirming their role in inhibiting the p97 signaling pathway in cells. In addition, the IC50 of compounds 4-6 against HCT116, RPMI-8226, and s180 proliferation were 0.24-6.9 µM with comparable potency as DBeQ. However, compounds 4-6 displayed low toxicity against the normal human colon cell line. Thus, compounds 6 and 7 were proved to be potential p97 inhibitors with less cytotoxicity. In vivo studies using the s180 xenograft model have demonstrated that compound 6 inhibited tumor growth, led to a significant reduction of p97 concentration in the serum and tumor, and indicated non-toxicity on the body weight and organ-to-brain weight ratios except for the spleen at the dose of 90 µmol/kg/day for 10 days. Furthermore, the present study indicated that compound 6 may not induce s180 mice myelosuppression often observed in the p97 inhibitors. Conclusion: Compound 6 displayed high binding affinity to p97, great p97 ATPase inhibition, selective cytotoxicity, remarkable anti-tumor effect, and upregulated safety, which improved the clinical potential of p97 inhibitors.

Neighborhood, social cohesion, and the Elderly's depression in Shanghai.

Neighborhood plays an important role in the provision of elderly care in the context of rapid population aging and dwindling traditional family support in China. This study investigates the association between neighborhood characteristics and depression and its mechanisms among older adults in Shanghai, focusing on social cohesion and social engagement. Based on data from the first wave of Shanghai Urban Neighborhood Survey (SUNS), we show that social cohesion is a channel through which neighborhood attributes are linked with the elderly's subjective well-being. Different from findings in Western societies, Chinese older adults living in neighborhoods of lower socioeconomic status are more likely to interact with their neighbors and thus perceive a higher level of social cohesion. Social cohesion, in turn, is associated with a lower rate of depression. We argue that housing policy in the pre-reform period that integrated work and housing led to the formation of unique Chinese neighborhoods, and that those living in socioeconomically disadvantaged neighborhoods have strong social ties, which moderate the negative consequences of living in a disadvantaged one. Moreover, a neighborhood with a lower dependency ratio provides more opportunities for volunteer participation which significantly associates with increased social cohesion and decreased depressive symptoms.