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1.
Arthritis Rheumatol ; 72(7): 1192-1202, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32134203

RESUMO

OBJECTIVE: The NLRP3 inflammasome is closely linked to the pathophysiology of a wide range of inflammatory diseases. This study was undertaken to identify small molecules that directly bind to NLRP3 in order to develop pharmacologic interventions for NLRP3-related diseases. METHODS: A structure-based virtual screening analysis was performed with ~62,800 compounds to select efficient NLRP3 inhibitors. The production of caspase 1-p10 and interleukin-1ß (IL-1ß) was measured by immunoblotting and enzyme-linked immunosorbent assay to examine NLRP3 inflammasome activation. Two gouty arthritis models and an air pouch inflammation model induced by monosodium urate monohydrate (MSU) crystal injection were used for in vivo experiments. Primary synovial fluid cells from gout patients were used to determine the relevance of NLRP3 inflammasome inhibition in human gout. RESULTS: Beta-carotene (provitamin A) suppressed the NLRP3 inflammasome activation induced by various activators, including MSU crystals, in mouse bone marrow-derived primary macrophages (P < 0.05). Surface plasmon resonance analysis demonstrated the direct binding of ß-carotene to the pyrin domain (PYD) of NLRP3 (KD = 3.41 × 10-6 ). Molecular modeling and mutation assays revealed the interaction mode between ß-carotene and the NLRP3 PYD. Inflammatory symptoms induced by MSU crystals were attenuated by oral administration of ß-carotene in gouty arthritis mouse models (P < 0.05), correlating with its suppressive effects on the NLRP3 inflammasome in inflamed tissues. Furthermore, ß-carotene reduced IL-1ß secretion from human synovial fluid cells isolated from gout patients (P < 0.05), showing its inhibitory efficacy in human gout. CONCLUSION: Our results present ß-carotene as a selective and direct inhibitor of NLRP3, and the binding of ß-carotene to NLRP3 PYD as a novel pharmacologic strategy to combat NLRP3 inflammasome-driven diseases, including gouty arthritis.


Assuntos
Artrite Gotosa/imunologia , Inflamassomos/antagonistas & inibidores , Inflamação/imunologia , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Provitaminas/farmacologia , beta Caroteno/farmacologia , Animais , Caspase 1/efeitos dos fármacos , Caspase 1/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Gota/imunologia , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/imunologia , Macrófagos/imunologia , Camundongos , Simulação de Acoplamento Molecular , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Domínio Pirina , Ressonância de Plasmônio de Superfície , Líquido Sinovial/citologia
2.
Mol Carcinog ; 58(1): 88-101, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30230030

RESUMO

Ras/Raf/MEKs/ERKs and PI3 K/Akt/mTOR signaling pathways have key roles in cancer development and growth processes, as well as in cancer malignance and chemoresistance. In this study, we screened the therapeutic potential of magnolin using 15 human cancer cell lines and combined magnolin sensitivity with the CCLE mutaome analysis for relevant mutation information. The results showed that magnolin efficacy on cell proliferation inhibition were lower in TOV-112D ovarian cancer cells than that in SKOV3 cells by G1 and G2/M cell cycle phase accumulation. Notably, magnolin suppressed colony growth of TOV-112D cells in soft agar, whereas colony growth of SKOV3 cells in soft agar was not affected by magnolin treatment. Interestingly, phospho-protein profiles in the MAPK and PI3 K signaling pathways indicated that SKOV3 cells showed marked increase of Akt phosphorylation at Thr308 and Ser473 and very weak ERK1/2 phosphorylation levels by EGF stimulation. The phospho-protein profiles in TOV-112D cells were the opposite of those of SKOV3 cells. Importantly, magnolin treatment suppressed phosphorylation of RSKs in TOV-112D, but not in SKOV3 cells. Moreover, magnolin increased SA-ß-galactosidase-positive cells in a dose-dependent manner in TOV-112D cells, but not in SKOV3 cells. Notably, oral administration of Shin-Yi fraction 1, which contained magnolin approximately 53%, suppressed TOV-112D cell growth in athymic nude mice by induction of p16Ink4a and p27Kip1 . Taken together, targeting of ERK1 and ERK2 is suitable for the treatment of ovarian cancer cells that do not harbor the constitutive active P13 K mutation and the loss-of-function mutations of the p16 and/or p53 tumor suppressor proteins.


Assuntos
Proliferação de Células/efeitos dos fármacos , Senescência Celular , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lignanas/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Neoplasias Ovarianas/patologia , Animais , Apoptose , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Clin Dent ; 15(1): 33-6, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15218714

RESUMO

OBJECTIVE: The purpose of this research was to compare the Dr. SEDOC toothbrush, tufted with super-tapered bristles, to the ADA standard toothbrush in three laboratory procedures designed to evaluate 1) the cleaning ability of toothbrush bristles at the gingival margin (GMC), 2) interproximal access efficacy (IAE) and plaque removal efficacy, or 3) subgingival access (SA) into, and removal of artificial plaque deposits from under the gingival margin. METHODOLOGY: Efficacy was tested using three published laboratory methods, with pressure-sensitive paper placed around simulated teeth, at a brushing pressure of 250 or 500 g, with horizontal or vertical brushing motions. Twenty-four tests on each toothbrush design were conducted, and results were statistically analyzed using ANOVA. RESULTS: In all three assays, the Dr. SEDOC toothbrush had a significantly superior (p < 0.001) efficacy mean value compared to the ADA toothbrush. CONCLUSION: The Dr. SEDOC toothbrush, with super-tapered bristles, offers the potential for improved cleaning and plaque removal compared to the ADA standard control toothbrush.


Assuntos
Dispositivos para o Cuidado Bucal Domiciliar , Escovação Dentária/instrumentação , American Dental Association , Análise de Variância , Dispositivos para o Cuidado Bucal Domiciliar/normas , Placa Dentária/terapia , Desenho de Equipamento , Gengivite/prevenção & controle , Humanos , Estados Unidos
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