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1.
J Adv Res ; 2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38565403

RESUMO

BACKGROUND: Purinergic P2 receptors, which can be divided into ionotropic P2X receptors and metabotropic P2Y receptors, mediate cellular signal transduction of purine or pyrimidine nucleoside triphosphates and diphosphate. Based on the wide expression of purinergic P2 receptors in tissues and organs, their significance in homeostatic maintenance, metabolism, nociceptive transmission, and other physiological processes is becoming increasingly evident, suggesting that targeting purinergic P2 receptors to regulate biological functions and signal transmission holds significant promise for disease treatment. AIM OF REVIEW: This review highlights the detailed mechanisms by which purinergic P2 receptors engage in physiological and pathological progress, as well as providing prospective strategies for discovering clinical drug candidates. KEY SCIENTIFIC CONCEPTS OF REVIEW: The purinergic P2 receptors regulate complex signaling and molecular mechanisms in nervous system, digestive system, immune system and as a result, controlling physical health states and disease progression. There has been a significant rise in research and development focused on purinergic P2 receptors, contributing to an increased number of drug candidates in clinical trials. A few influential pioneers have laid the foundation for advancements in the evaluation, development, and of novel purinergic P2 receptors modulators, including agonists, antagonists, pharmaceutical compositions and combination strategies, despite the different scaffolds of these drug candidates. These advancements hold great potential for improving therapeutic outcomes by specifically targeting purinergic P2 receptors.

2.
J Med Chem ; 66(9): 6315-6332, 2023 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-37078976

RESUMO

As a member of purinoceptors, the P2Y6 receptor (P2Y6R) plays a crucial role in modulating immune signals and has been considered as a potential therapeutic target for inflammatory diseases. On the basis of the speculated probable conformation and binding determinants of P2Y6R, a hierarchical strategy that combines virtual screening, bioassays, and chemical optimization was presented. A potent P2Y6R antagonist (compound 50) was identified to possess excellent antagonistic activity (IC50 = 5.914 nM) and high selectivity. In addition, binding assays and chemical pull-down experiments confirmed that compound 50 was nicely bound to P2Y6R. Notably, compound 50 could effectively ameliorate DSS-induced ulcerative colitis in mice through inhibiting the activation of NLRP3 inflammasome in colon tissues. Moreover, treatment with compound 50 reduced LPS-induced pulmonary edema and infiltration of inflammatory cells in mice. These findings suggest that compound 50 could serve as a specific P2Y6R antagonist for treating inflammatory diseases and deserve further optimization studies.


Assuntos
Colite Ulcerativa , Colite , Animais , Camundongos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Sulfato de Dextrana , Inflamassomos/metabolismo , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR
3.
Biosensors (Basel) ; 12(10)2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36291012

RESUMO

Establishing a systematic molecular information analysis strategy for cell culture models is of great significance for drug development and tissue engineering technologies. Here, we fabricated single silver nanowires with high surface-enhanced Raman scattering activity to extract SERS spectra in situ from two-dimensional (2D) and three-dimensional (3D) cell culture models. The silver nanowires were super long, flexible and thin enough to penetrate through multiple cells. A single silver nanowire was used in combination with a four-dimensional microcontroller as a cell endoscope for spectrally analyzing the components in cell culture models. Then, we adopted a machine learning algorithm to analyze the obtained spectra. Our results show that the abundance of proteins differs significantly between the 2D and 3D models, and that nucleic acid-rich and protein-rich regions can be distinguished with satisfactory accuracy.


Assuntos
Nanofios , Ácidos Nucleicos , Prata , Técnicas de Cultura de Células em Três Dimensões , Análise Espectral Raman/métodos , Imagem Molecular
4.
Pathol Res Pract ; : 153278, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33549364

RESUMO

This article has been withdrawn: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The publisher regrets that an error occurred which led to the premature publication of this paper. The publisher apologizes to the authors and the readers for this unfortunate error.

5.
PLoS One ; 14(9): e0221872, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31490974

RESUMO

The primary objective of this study is to compare pedestrian evacuation strategies in the large-scale public space (LPS) using microscopic model. Data were collected by video recording from Tian-yi square for 36 hours in city of Ningbo, China. A pedestrian evacuation simulation model was developed based on the social force model (SFM). The simulation model parameters, such as reaction time, elasticity coefficient, sliding coefficient, et al, were calibrated using the real data extracted from the video. Five evacuation strategies, strategy 1 (S1) to strategy 5 (S5) involving distance, density and capacity factors were simulated and compared by indicators of evacuation time and channel utilization rate, as well as the evacuation efficiency. The simulation model parameters calibration results showed that a) the pedestrians walking speed is 1.0 ~ 1.5m/s; b) the pedestrians walking diameter is 0.3 ~ 0.4m; c) the frequency of pedestrian arrival and departure followed multi-normal distribution. The simulation results showed that, (a) in terms of total evacuation time, the performance of S4 and S5 which considering the capacity and density factors were best in all evacuation scenarios, the performance of S3 which only considering the density factor was the worst, relatively, and S1 and S2 which considering the distance factor were in the middle. (b) the utilization rate of channels under S5 strategy was better than other strategies, which performs best in the balance of evacuation. S3 strategy was the worst, and S1, S2 and S4 were in the middle. (c) in terms of the evacuation efficiency, when the number of evacuees is within 2, 500 peds, the S1 and S2 strategy which considering the distance factor have best evacuation efficiency than other strategies. And when the number of evacuees is above 2, 500 peds, the S4 and S5 strategy which considering the capacity factor are better than others.


Assuntos
Comportamento de Escolha , Meio Ambiente , Modelos Teóricos , Pedestres/psicologia , Humanos , Segurança , Caminhada
6.
Artif Cells Nanomed Biotechnol ; 47(1): 2500-2506, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31203648

RESUMO

Angiotensin I-Converting Enzyme (ACE, CD143) Gene plays a crucial role in the pathology of carcinomas in many cancers including colorectal cancer (CRC). However, the methylation of ACE was rarely reported. In this study, our purpose was to investigate the methylation status of ACE and explored its prognostic value in CRC. The expression of ACE was detected by quantitative real-time polymerase chain reaction (qRT-PCR) analysis while the methylation status of ACE was measured via methylation-specific polymerase chain reaction (MSP). The result demonstrated that ACE expression was up-regulated in tumour tissues and HT-29 cells compared with the controls. ACE was also confirmed to be hypomethylated in CRC. Next, we evaluated the influence of ACE hypomethylation on cell growth. It was proved to be a favourable factor for the cell proliferation, cell colony forming, but an inhibitor for the cell apoptosis of CRC cells according to MST assay, colony forming assay and flow cytometry assay. ACE hypomethylation was also considered to be related to the prognosis of CRC through Cox regression analysis. Taken together, the over-expression of ACE was regulated by its hypomethylation and the ACE hypomethylation might be an independent prognostic indicator in CRC.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Peptidil Dipeptidase A/genética , Estudos de Casos e Controles , Proliferação de Células/genética , Neoplasias Colorretais/diagnóstico , Metilação de DNA , Feminino , Células HT29 , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida
7.
Pain ; 159(7): 1224-1234, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29533388

RESUMO

It is well established that FKBP51 regulates the stress system by modulating the sensitivity of the glucocorticoid receptor to stress hormones. Recently, we have demonstrated that FKBP51 also drives long-term inflammatory pain states in male mice by modulating glucocorticoid signalling at spinal cord level. Here, we explored the potential of FKBP51 as a new pharmacological target for the treatment of persistent pain across the sexes. First, we demonstrated that FKBP51 regulates long-term pain states of different aetiologies independently of sex. Deletion of FKBP51 reduced the mechanical hypersensitivity seen in joint inflammatory and neuropathic pain states in female and male mice. Furthermore, FKBP51 deletion also reduced the hypersensitivity seen in a translational model of chemotherapy-induced pain. Interestingly, these 3 pain states were associated with changes in glucocorticoid signalling, as indicated by the increased expression, at spinal cord level, of the glucocorticoid receptor isoform associated with glucocorticoid resistance, GRß, and increased levels of plasma corticosterone. These pain states were also accompanied by an upregulation of interleukin-6 in the spinal cord. Crucially, we were able to pharmacologically reduce the severity of the mechanical hypersensitivity seen in these 3 models of persistent pain with the unique FKBP51 ligand SAFit2. When SAFit2 was combined with a state-of-the-art vesicular phospholipid gel formulation for slow release, a single injection of SAFit2 offered pain relief for at least 7 days. We therefore propose the pharmacological blockade of FKBP51 as a new approach for the treatment of persistent pain across sexes, likely in humans as well as rodents.


Assuntos
Inflamação/metabolismo , Neuralgia/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Feminino , Glucocorticoides/metabolismo , Inflamação/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Knockout , Neuralgia/genética , Receptores de Glucocorticoides/metabolismo , Medula Espinal/metabolismo , Proteínas de Ligação a Tacrolimo/genética
8.
Nat Commun ; 8(1): 1725, 2017 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-29170369

RESUMO

The co-chaperone FKBP5 is a stress-responsive protein-regulating stress reactivity, and its genetic variants are associated with T2D related traits and other stress-related disorders. Here we show that FKBP51 plays a role in energy and glucose homeostasis. Fkbp5 knockout (51KO) mice are protected from high-fat diet-induced weight gain, show improved glucose tolerance and increased insulin signaling in skeletal muscle. Chronic treatment with a novel FKBP51 antagonist, SAFit2, recapitulates the effects of FKBP51 deletion on both body weight regulation and glucose tolerance. Using shorter SAFit2 treatment, we show that glucose tolerance improvement precedes the reduction in body weight. Mechanistically, we identify a novel association between FKBP51 and AS160, a substrate of AKT2 that is involved in glucose uptake. FKBP51 antagonism increases the phosphorylation of AS160, increases glucose transporter 4 expression at the plasma membrane, and ultimately enhances glucose uptake in skeletal myotubes. We propose FKBP51 as a mediator between stress and T2D development, and potential target for therapeutic approaches.


Assuntos
Proteínas Ativadoras de GTPase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Transporte Biológico Ativo , Dieta Hiperlipídica , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Fibras Musculares Esqueléticas/metabolismo , Fosforilação , Transdução de Sinais , Estresse Fisiológico , Proteínas de Ligação a Tacrolimo/deficiência , Proteínas de Ligação a Tacrolimo/genética , Aumento de Peso
9.
Opt Express ; 25(2): 799-809, 2017 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-28157968

RESUMO

Single-photon avalanche diode (SPAD) is a promising photosensor because of its high sensitivity to optical signals in weak illuminance environment. Recently, it has drawn much attention from researchers in visible light communications (VLC). However, existing literature only deals with the simplified channel model, which only considers the effects of Poisson noise introduced by SPAD, but neglects other noise sources. Specifically, when an analog SPAD detector is applied, there exists Gaussian thermal noise generated by the transimpedance amplifier (TIA) and the digital-to-analog converter (D/A). Therefore, in this paper, we propose an SPAD-based VLC system with pulse-amplitude-modulation (PAM) under Poisson-Gaussian mixed noise model, where Gaussian-distributed thermal noise at the receiver is also investigated. The closed-form conditional likelihood of received signals is derived using the Laplace transform and the saddle-point approximation method, and the corresponding quasi-maximum-likelihood (quasi-ML) detector is proposed. Furthermore, the Poisson-Gaussian-distributed signals are converted to Gaussian variables with the aid of the generalized Anscombe transform (GAT), leading to an equivalent additive white Gaussian noise (AWGN) channel, and a hard-decision-based detector is invoked. Simulation results demonstrate that, the proposed GAT-based detector can reduce the computational complexity with marginal performance loss compared with the proposed quasi-ML detector, and both detectors are capable of accurately demodulating the SPAD-based PAM signals.

10.
Curr Pharm Des ; 22(46): 6982-6987, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27875973

RESUMO

Earlier we reported the identification of diarylpyrimidine-quinolone hybrids as a new class of HIV-1 NNRTIs. A few of these hybrids displayed moderate inhibitory activity against wt HIV-1 replication at submicromolar level, however, all of them lacked inhibitory activity against the double mutant virus (K103N/Y181C), which is the most prevalent NNRTI resistant-associated double mutant observed in the clinic. In the present study, we designed and synthesized a new series of diarylpyrimidine-quinolone hybrids featuring a halogen group at C-6' position of quinolone ring. The biological results indicated that most of these hybrids could inhibit wt HIV-1 replication at nanomolar level ranging from 0.088 to 0.0096 µM. The most promising hybrid 5c displayed a significant EC50 value of 0.0096 µM against HIV-1 IIIB and of 0.98 µM against K103N/Y181C. Further docking studies revealed that these hybrids could be well located in the hydrophobic NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid scaffold in the molecules. These promising results suggested a high potential to further develop these hybrids as next-generation NNRTIs with improved antiviral efficacy and resistance profile.


Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV/efeitos dos fármacos , Pirimidinas/farmacologia , Quinolonas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Farmacorresistência Viral/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Pirimidinas/química , Quinolonas/química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
11.
Eur J Med Chem ; 102: 215-22, 2015 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-26276435

RESUMO

Based on molecular simulation, the etravirine-VRX-480773 hybrids previously disclosed by our group were optimized to yield novel pyrimidine sulfonylacetanilides 8 with improved activity against a panel of seven clinically relevant single and double mutant strains of HIV-1. The improvement in potency in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits the reverse transcriptase (RT), and represents a remarkable step forward in the development of anti-HIV drugs.


Assuntos
Acetanilidas/síntese química , Acetanilidas/farmacologia , Fármacos Anti-HIV/farmacologia , Sequência Conservada/efeitos dos fármacos , HIV-1/efeitos dos fármacos , HIV-1/genética , Mutação , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Acetanilidas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , HIV-1/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Células Tumorais Cultivadas
12.
Bioorg Med Chem ; 23(15): 4248-4255, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26162497

RESUMO

A novel series of etravirine-VRX-480773 hybrids were designed using structure-guided molecular hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N-(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC50=0.24 , SI>1225), was more potent than delavirdine (EC50=0.66 µM, SI>67) in the anti-HIV-1 in vitro cellular assay. Studies of structure-activity relationships established a correlation between anti-HIV activity and the substitution pattern of the acetanilide group.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Inibidores da Transcriptase Reversa/química , Acetanilidas/química , Fármacos Anti-HIV/síntese química , Linhagem Celular , Técnicas de Química Sintética , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Humanos , Simulação de Dinâmica Molecular , Nitrilas , Piridazinas/química , Pirimidinas , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Triazóis/química
13.
Eur J Med Chem ; 97: 1-9, 2015 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-25935383

RESUMO

A novel series of piperidin-4-yl-aminopyrimidine derivatives were designed fusing the pharmacophore templates of etravirine-VRX-480773 hybrids our group previously described and piperidine-linked aminopyrimidines. Most compounds displayed significantly improved activity against wild-type HIV-1 with EC50 values in single-digit nanomolar concentrations compared to etravirine-VRX-480773 hybrids. Selected compounds were also evaluated for activity against reverse transcriptase, and had lower IC50 values than that of nevirapine. The improved potency observed in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits reverse transcriptase, and represents a remarkable step forward in the development of AIDS therapeutics.


Assuntos
Fármacos Anti-HIV/síntese química , Descoberta de Drogas , Transcriptase Reversa do HIV/antagonistas & inibidores , Piperidinas/síntese química , Pirimidinas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Células Cultivadas , Humanos , Estrutura Molecular , Nitrilas , Piperidinas/química , Piperidinas/farmacologia , Piridazinas/química , Piridazinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade
14.
Bioorg Med Chem ; 23(13): 3860-8, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25907370

RESUMO

A molecular hybridization approach is a powerful tool in the design of new molecules with improved affinity and efficacy. In this context, a series of diarylpyrimidine-quinolone hybrids were synthesized and evaluated against both wt HIV-1 and mutant viral strains. The most active hybrid 5a displayed an EC50 value of 0.28±0.07µM against HIV-1 IIIB. A couple of enzyme-based assays clearly pinpoint a RT-targeted mechanism of action. Docking studies revealed that these hybrids could be well located in the NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid moiety in the molecules.


Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Quinolonas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Sítios de Ligação , Linhagem Celular , Desenho de Fármacos , Células Precursoras de Granulócitos/efeitos dos fármacos , Células Precursoras de Granulócitos/patologia , Células Precursoras de Granulócitos/virologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , HIV-1/crescimento & desenvolvimento , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Pirimidinas/síntese química , Quinolonas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Relação Estrutura-Atividade , Acetato de Tetradecanoilforbol/farmacologia , Latência Viral/efeitos dos fármacos
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