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1.
Elife ; 132024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38275142

RESUMO

Organ formation requires precise regulation of cell cycle and morphogenetic events. Using the Drosophila embryonic salivary gland (SG) as a model, we uncover the role of the SP1/KLF transcription factor Huckebein (Hkb) in coordinating cell cycle regulation and morphogenesis. The hkb mutant SG exhibits defects in invagination positioning and organ size due to the abnormal death of SG cells. Normal SG development involves distal-to-proximal progression of endoreplication (endocycle), whereas hkb mutant SG cells undergo abnormal cell division, leading to cell death. Hkb represses the expression of key cell cycle and pro-apoptotic genes in the SG. Knockdown of cyclin E or cyclin-dependent kinase 1, or overexpression of fizzy-related rescues most of the morphogenetic defects observed in the hkb mutant SG. These results indicate that Hkb plays a critical role in controlling endoreplication by regulating the transcription of key cell cycle effectors to ensure proper organ formation.


Assuntos
Proteínas de Drosophila , Animais , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila/genética , Divisão Celular , Glândulas Salivares , Morfogênese/genética , Ciclo Celular/genética
2.
Bioorg Med Chem Lett ; 28(14): 2432-2435, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29929881

RESUMO

Radiosynthesis and in vivo evaluation of [11C]4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (methoxy analogue of valdecoxib, [11C]MOV), a COX-2 inhibitor, was conducted in rat and baboon. Synthesis of the reference standard MOV (3), and its desmethyl precursor 2 for radiolabeling were performed using 1,2-diphenylethan-1-one as the starting material in five steps with 15% overall yield. Radiosynthesis of [11C]MOV was accomplished in 40 ±â€¯10% yield and >99% radiochemical purity by reacting the precursor 2 in dimethyl formamide (DMF) with [11C]CH3I followed by removal of the dimethoxytrityl (DMT) protective group using trifluroacetic acid. PET studies in anesthetized baboon showed very low uptake and homogeneous distribution of [11C]MOV in brain. The radioligand underwent rapid metabolism in baboon plasma. MicroPET studies in male Sprague Dawley rats revealed [11C]MOV binding in lower thorax. The tracer binding in rats was partially blocked in heart and duodenum by the administration of 1 mg/kg oral dose of COX-2 inhibitor valdecoxib.


Assuntos
Celecoxib/química , Inibidores de Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/análise , Ciclo-Oxigenase 2/metabolismo , Isoxazóis/química , Tomografia por Emissão de Pósitrons , Sulfonamidas/química , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Radioisótopos de Carbono , Celecoxib/síntese química , Celecoxib/farmacocinética , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Isoxazóis/síntese química , Isoxazóis/farmacocinética , Masculino , Estrutura Molecular , Papio , Ratos , Ratos Sprague-Dawley , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética
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