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1.
Nature ; 542(7639): 49-54, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-28024299

RESUMO

Lymphatic vessels are lined by lymphatic endothelial cells (LECs), and are critical for health. However, the role of metabolism in lymphatic development has not yet been elucidated. Here we report that in transgenic mouse models, LEC-specific loss of CPT1A, a rate-controlling enzyme in fatty acid ß-oxidation, impairs lymphatic development. LECs use fatty acid ß-oxidation to proliferate and for epigenetic regulation of lymphatic marker expression during LEC differentiation. Mechanistically, the transcription factor PROX1 upregulates CPT1A expression, which increases acetyl coenzyme A production dependent on fatty acid ß-oxidation. Acetyl coenzyme A is used by the histone acetyltransferase p300 to acetylate histones at lymphangiogenic genes. PROX1-p300 interaction facilitates preferential histone acetylation at PROX1-target genes. Through this metabolism-dependent mechanism, PROX1 mediates epigenetic changes that promote lymphangiogenesis. Notably, blockade of CPT1 enzymes inhibits injury-induced lymphangiogenesis, and replenishing acetyl coenzyme A by supplementing acetate rescues this process in vivo.


Assuntos
Ácidos Graxos/química , Ácidos Graxos/metabolismo , Linfangiogênese , Vasos Linfáticos/citologia , Vasos Linfáticos/metabolismo , Acetatos/farmacologia , Acetilcoenzima A/metabolismo , Acetilação/efeitos dos fármacos , Animais , Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Epigênese Genética , Feminino , Histonas/metabolismo , Proteínas de Homeodomínio/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Linfangiogênese/efeitos dos fármacos , Linfangiogênese/genética , Vasos Linfáticos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução/efeitos dos fármacos , Biossíntese de Proteínas , Transcrição Gênica , Proteínas Supressoras de Tumor/metabolismo , Artérias Umbilicais/citologia , Regulação para Cima
2.
Bioresour Technol ; 289: 121772, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31307865

RESUMO

The present work aims to develop a magnetic biocatalyst for customized production of nucleoside analogues using mutant His-tagged purine 2'-deoxyribosyltransferase from Trypanosoma brucei (TbPDTV11S) immobilized onto Ni2+ chelate magnetic iron oxide porous microparticles (MTbPDTV11S). Biochemical characterization revealed MTbPDTV11S5 as optimal candidate for further studies (10,552 IU g-1; retained activity 54% at 50 °C and pH 6.5). Interestingly, MTbPDTV11S5 displayed the highest activity value described up to date for an immobilized NDT. Moreover, MTbPDTV11S5 was successfully employed in the one-pot, one-step production of different therapeutic nucleoside analogues, such as cladribine or 2'-deoxy-2-fluoroadenosine, among others. Finally, MTbPDTV11S5 proved to be stable when stored at 50 °C for 8 h and pH 6.0 and reusable up to 10 times without negligible loss of activity in the enzymatic production of the antitumor prodrug 2'-deoxy-2-fluoroadenosine.


Assuntos
Pentosiltransferases/metabolismo , Quelantes , Desoxiadenosinas , Estabilidade Enzimática , Enzimas Imobilizadas/metabolismo , Compostos Férricos , Magnetismo , Nucleosídeos , Purinas , Temperatura
3.
Biomed Res Int ; 2015: 169234, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26090386

RESUMO

The studies of drugs that could constitute a palliative to spinal cord injury (SCI) are a continuous and increasing demand in biomedicine field from developed societies. Recently we described the chemical synthesis and antiglioma activity of synthetic glycosides. A synthetic sulfated glycolipid (here IG20) has shown chemical stability, solubility in polar solvents, and high inhibitory capacity over glioma growth. We have used mass spectrometry (MS) to monitor IG20 (m/z = 550.3) in cells and tissues of the central nervous system (CNS) that are involved in SCI recovery. IG20 was detected by MS in serum and homogenates from CNS tissue of rats, though in the latter a previous deproteinization step was required. The pharmacokinetic parameters of serum clearance at 24 h and half-life at 4 h were determined for synthetic glycoside in the adult rat using MS. A local administration of the drug near of spinal lesion site is proposed.


Assuntos
Glicolipídeos/administração & dosagem , Espectrometria de Massas , Traumatismos da Medula Espinal/sangue , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Modelos Animais de Doenças , Glicolipídeos/síntese química , Glicolipídeos/farmacocinética , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/patologia
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