RESUMO
Raloxifene, a selective estrogen receptor modulator, displays benefits for Alzheimer's disease (AD) prevention in postmenopausal women as hormonal changes during menopause have the potential to influence AD pathogenesis, but the underlying mechanism of its neuroprotection is not entirely clear. In this study, the effects of raloxifene on amyloid-ß (Aß) amyloidogenesis were evaluated. The results demonstrated that raloxifene inhibits Aß42 aggregation and destabilizes preformed Aß42 fibrils through directly interacting with the N-terminus and middle domains of Aß42 peptides. Consequently, raloxifene not only reduces direct toxicity of Aß42 in HT22 neuronal cells, but also suppresses expressions of tumor necrosis factor-α and transforming growth factor-ß induced by Aß42 peptides, and then alleviates microglia-mediated indirect toxicity of Aß42 to HT22 neuronal cells. Our results suggested an alternative possible explanation for the neuroprotective activity of raloxifene in AD prevention.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/toxicidade , Agregados Proteicos/efeitos dos fármacos , Cloridrato de Raloxifeno/farmacologia , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Microglia/citologia , Microglia/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/química , Agregação Patológica de Proteínas/metabolismo , Domínios Proteicos , Cloridrato de Raloxifeno/química , Fator de Crescimento Transformador beta/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
The first proteolysis targeting chimeras for the intracellular elimination of transforming growth factor-ß1 (TGF-ß1), which contributes to various diseases, are described. The appropriately designed DT-6 could efficiently degrade intracellular TGF-ß1, and inhibit M2 macrophage induced epithelial to mesenchymal transition and invasive migration of cancer cells.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Macrófagos/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Transição Epitelial-Mesenquimal , Células Hep G2 , Humanos , Invasividade NeoplásicaRESUMO
Blockade of immune checkpoint PD-1/PD-L1 facilitates the rescue of immune escapes of tumor cells. Though various monoclonal antibodies have been approved for clinical therapy, the development of small molecular inhibitors lags behind antibodies partially owing to the challenges of protein-protein interaction (PPI) blocker design. In this work, we adopted the skeleton of natural cyclopeptidic antibiotics gramicidin S as the start point for PD-1/PD-L1 inhibitor exploring and discovered a series of novel cyclopeptides that could interfere with the PPI of PD-1/PD-L1 based on several rounds of structural design and optimization. The representative active cyclopeptide 66 can bind two PD-L1 and efficiently block the PD-1/PD-L1 interaction, recruit the immune cells to the tumor cells, enhance their killing against tumor cells by promoting the release of granzyme B and perforin, and display significant CD8+ T cell-dependent tumor suppression activity in vivo.