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1.
J Med Chem ; 67(5): 4083-4099, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38348878

RESUMO

Inhibition of the PD-1/PD-L1 interaction through small-molecule inhibitors is a promising therapeutic approach in cancer immunotherapy. Herein, we utilized BMS-202 as the lead compound to develop a series of novel PD-1/PD-L1 small-molecule inhibitors with a naphthyridin scaffold. Among these compounds, X14 displayed the most potent inhibitory activity for the PD-1/PD-L1 interaction (IC50 = 15.73 nM). Furthermore, X14 exhibited good binding affinity to both human PD-L1 (KD = 14.62 nM) and mouse PD-L1 (KD = 392 nM). In particular, X14 showed favorable pharmacokinetic properties (oral bioavailability, F = 58.0%). In the 4T1 (mouse breast cancer cells) syngeneic mouse model, intragastric administration of X14 at 10 mg/kg displayed significant antitumor efficacy (TGI = 66%). Mechanistic investigations revealed that X14 effectively enhanced T-cell infiltration within the tumor microenvironment. Our study demonstrates that compound X14 exhibits potential as a candidate compound for the development of orally effective small-molecule inhibitors targeting PD-1/PD-L1.


Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Camundongos , Animais , Antígeno B7-H1 , Receptor de Morte Celular Programada 1/metabolismo , Imunoterapia , Neoplasias/terapia
2.
Sci Rep ; 12(1): 14378, 2022 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-35999245

RESUMO

An increasing number of studies have been devoted to electroencephalogram (EEG) identity recognition since EEG signals are not easily stolen. Most of the existing studies on EEG person identification have only addressed brain signals in a single state, depending upon specific and repetitive sensory stimuli. However, in reality, human states are diverse and rapidly changing, which limits their practicality in realistic settings. Among many potential solutions, transformer is widely used and achieves an excellent performance in natural language processing, which demonstrates the outstanding ability of the attention mechanism to model temporal signals. In this paper, we propose a transformer-based approach for the EEG person identification task that extracts features in the temporal and spatial domains using a self-attention mechanism. We conduct an extensive study to evaluate the generalization ability of the proposed method among different states. Our method is compared with the most advanced EEG biometrics techniques and the results show that our method reaches state-of-the-art results. Notably, we do not need to extract any features manually.


Assuntos
Interfaces Cérebro-Computador , Eletroencefalografia , Encéfalo , Eletroencefalografia/métodos , Humanos
3.
Neurosci Lett ; 398(3): 268-73, 2006 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-16448753

RESUMO

Over-activation of ionotropic glutamate receptors can cause an excessive influx of calcium ions into neurons, which subsequently triggers the degeneration and death of cells in a process known as excitotoxicity. Here, we examined the effects of modulating ionotropic glutamate receptors and L-type voltage-gated calcium channels (L-VGCC) on the expression and activation of c-Jun in hippocampus of SD rats after transient global ischemia. The total protein of c-Jun was altered by ischemia-reperfusion and reached its high levels at 3-6 h of reperfusion. However, the increased expression was prevented by pretreatment of ketamine (a non-competitive N-methyl-D-aspartate (NMDA) receptors antagonist) or nifedipine (a blocker of L-VGCC), but not by 6,7-dinitroquinoxaline-2,3(1H,4H)-dione (DNQX), an AMPA/KA receptor antagonist. On the other hand, c-Jun phosphorylation was significantly increased 3 h after reperfusion, which was inhibited by DNQX, but not ketamine or nifedipine. AP-1 binding activity reactions were also performed by electrophoretic mobility shift assay (EMSA), which detected similar results as those in Western blotting. Our results clearly showed that c-Jun expression is NMDA receptor/L-VGCC-dependent and c-Jun activation is AMPA/KA receptor-dependent, which expands our knowledge of the JNK-c-Jun signaling pathway in ischemic brain damage.


Assuntos
Canais de Cálcio Tipo L/fisiologia , Hipocampo/metabolismo , Ataque Isquêmico Transitório/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Receptores de AMPA/fisiologia , Receptores de Ácido Caínico/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Estenose das Carótidas/complicações , Ativação Enzimática , Ataque Isquêmico Transitório/etiologia , Proteínas Quinases JNK Ativadas por Mitógeno/biossíntese , Ketamina/farmacologia , Masculino , Nifedipino/farmacologia , Fosforilação , Ligação Proteica , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/antagonistas & inibidores , Receptores de Ácido Caínico/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Reperfusão , Fator de Transcrição AP-1/metabolismo
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