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1.
Chemistry ; 23(49): 11945-11954, 2017 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-28631855

RESUMO

Vγ9Vδ2 T cells play an important role in the cross talk of the innate and adaptive immune system. For their activation by phosphoantigens (PAgs), both cell surface receptors, the eponymous Vγ9Vδ2 T cell antigen receptors (Vγ9Vδ2 TCRs) on Vγ9Vδ2 T cells and butyrophilin 3A1 (BTN3A1) on the phosphoantigen-"presenting" cell, are mandatory. To find yet undetected but further contributing proteins, a biotinylated, photo-crosslinkable benzophenone probe BioBP-HMBPP (2) was synthesized from a known allyl alcohol in nine steps and overall 16 % yield. 2 is based on the picomolar PAg (E)-4-hydroxy-3-methylbut-2-enyl diphosphate (HMBPP, 1). Laser irradiation of 2 at 308 nm initiated the photo-crosslinking reaction with proteins. When the B30.2 domain of BTN3A1, which contains a positively charged PAg-binding pocket, was exposed to increasing amounts of HMBPP (1), labeling by BioBP-HMBPP (2) was reduced significantly. Because BSA labeling was not impaired, 2 clearly binds to the same site as natural ligand 1. Thus, BioBP-HMBPP (2) is a suitable tool to identify co-ligands or receptors involved in PAg-mediated T cell activation.


Assuntos
Antígenos CD/metabolismo , Biotina/análogos & derivados , Butirofilinas/metabolismo , Compostos Organofosforados/química , Animais , Antígenos/imunologia , Antígenos/metabolismo , Antígenos CD/química , Antígenos de Diferenciação de Linfócitos T/metabolismo , Biotina/síntese química , Biotinilação/efeitos da radiação , Butirofilinas/química , Bovinos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Humanos , Lasers , Lectinas Tipo C/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Compostos Organofosforados/síntese química , Compostos Organofosforados/farmacologia , Ligação Proteica , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Espectrofotometria , Linfócitos T/citologia , Linfócitos T/metabolismo , Regulação para Cima/efeitos dos fármacos
2.
PLoS One ; 10(11): e0142932, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26565402

RESUMO

Cell protection against different noxious stimuli like oxidative stress or chemical toxins plays a central role in the treatment of many diseases. The inducible heme oxygenase isoform, heme oxygenase-1 (HO-1), is known to protect cells against a variety of harmful conditions including apoptosis. Because a number of medium strong electrophiles from a series of α-X-substituted 2',3,4,4'-tetramethoxychalcones (α-X-TMCs, X = H, F, Cl, Br, I, CN, Me, p-NO2-C6H4, Ph, p-OMe-C6H4, NO2, CF3, COOEt, COOH) had proven to activate Nrf2 resulting in HO-1 induction and inhibit NF-κB downstream target genes, their protective effect against staurosporine induced apoptosis and reactive oxygen species (ROS) production was investigated. RAW264.7 macrophages treated with 19 different chalcones (15 α-X-TMCs, chalcone, 2'-hydroxychalcone, calythropsin and 2'-hydroxy-3,4,4'-trimethoxychalcone) prior to staurosporine treatment were analyzed for apoptosis and ROS production, as well as HO-1 protein expression and enzyme activity. Additionally, Nrf2 and NF-κB activity was assessed. We found that amongst all tested chalcones only E-α-(4-methoxyphenyl)-2',3,4,4'-tetramethoxychalcone (E-α-p-OMe-C6H4-TMC) demonstrated a distinct, statistically significant antiapoptotic effect in a dose dependent manner, showing no toxic effects, while its double bond isomer Z-α-p-OMe-C6H4-TMC displayed no significant activity. Also, E-α-p-OMe-C6H4-TMC induced HO-1 protein expression and increased HO-1 activity, whilst inhibition of HO-1 by SnPP-IX abolished its antiapoptotic effect. The only weakly electrophilic chalcone E-α-p-OMe-C6H4-TMC reduced the staurosporine triggered formation of ROS, while inducing the translocation of Nrf2 into the nucleus. Furthermore, staurosporine induced NF-κB activity was attenuated following E-α-p-OMe-C6H4-TMC treatment. Overall, E-α-p-OMe-C6H4-TMC demonstrated its effective cytoprotective potential via a non-toxic induction of HO-1 in RAW264.7 macrophages. The observed cytoprotective effect may partly be related to both, the activation of the Nrf2- and inhibition of the NF-κB pathway.


Assuntos
Chalconas/química , Heme Oxigenase-1/efeitos dos fármacos , Proteínas de Membrana/efeitos dos fármacos , Animais , Apoptose , Linhagem Celular , Chalcona/análogos & derivados , Chalcona/química , Cristalografia por Raios X , Citoproteção/efeitos dos fármacos , Relação Dose-Resposta a Droga , Citometria de Fluxo , Regulação da Expressão Gênica , Macrófagos/efeitos dos fármacos , Camundongos , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Subunidade p50 de NF-kappa B/antagonistas & inibidores , Estresse Oxidativo , Transporte Proteico , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo
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