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1.
J Am Chem Soc ; 145(40): 21841-21850, 2023 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-37782839

RESUMO

Magnesium(II) plays catalytic, structural, regulatory, and signaling roles in living organisms. Abnormal levels of this metal have been associated with numerous pathologies, including cardiovascular disease, diabetes, metabolic syndrome, immunodeficiency, cancer, and, most recently, liver pathologies affecting humans. The role of Mg2+ in the pathophysiology of liver disease, however, has been occluded by concomitant changes in concentration of interfering divalent cations, such as Ca2+, which complicates the interpretation of experiments conducted with existing molecular Mg2+ indicators. Herein, we introduce a new quinoline-based fluorescent sensor, MagZet1, that displays a shift in its excitation and emission wavelengths, affording ratiometric detection of cellular Mg2+ by both fluorescence microscopy and flow cytometry. The new sensor binds the target metal with a submillimolar dissociation constant─well suited for detection of changes in free Mg2+ in cells─and displays a 10-fold selectivity against Ca2+. Furthermore, the fluorescence ratio is insensitive to changes in pH in the physiological range, providing an overall superior performance over existing indicators. We provide insights into the metal selectivity profile of the new sensor based on computational modeling, and we apply it to shed light on a decrease in cytosolic free Mg2+ and altered expression of metal transporters in cellular models of drug-induced liver injury caused by acetaminophen overdose.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Magnésio , Humanos , Magnésio/química , Acetaminofen/toxicidade , Corantes Fluorescentes/química
2.
Org Lett ; 23(2): 559-564, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33410700

RESUMO

An auto-tandem catalytic double allylic rearrangement of N-alloc-N-allyl ynamides was developed. This reaction proceeds through two separate and distinct catalytic cycles with both decarboxylative Pd-π-allyl and Pd(0)-promoted aza-Claisen rearrangements occurring. A detailed mechanistic study supported by computations highlights these two separate mechanisms. Previously unreported reversible C-N ionization and a Pd(0)-catalyzed [3,3]-sigmatropic rearrangement were discovered. This study provides new reaction pathways for both π-allyl and sigmatropic rearrangements.

3.
Dis Model Mech ; 11(7)2018 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-29929962

RESUMO

Familial dysautonomia (FD) is an autosomal recessive disorder marked by developmental and progressive neuropathies. It is caused by an intronic point-mutation in the IKBKAP/ELP1 gene, which encodes the inhibitor of κB kinase complex-associated protein (IKAP, also called ELP1), a component of the elongator complex. Owing to variation in tissue-specific splicing, the mutation primarily affects the nervous system. One of the most debilitating hallmarks of FD that affects patients' quality of life is progressive blindness. To determine the pathophysiological mechanisms that are triggered by the absence of IKAP in the retina, we generated retina-specific Ikbkap conditional knockout (CKO) mice using Pax6-Cre, which abolished Ikbkap expression in all cell types of the retina. Although sensory and autonomic neuropathies in FD are known to be developmental in origin, the loss of IKAP in the retina did not affect its development, demonstrating that IKAP is not required for retinal development. The loss of IKAP caused progressive degeneration of retinal ganglion cells (RGCs) by 1 month of age. Mitochondrial membrane integrity was breached in RGCs, and later in other retinal neurons. In Ikbkap CKO retinas, mitochondria were depolarized, and complex I function and ATP were significantly reduced. Although mitochondrial impairment was detected in all Ikbkap-deficient retinal neurons, RGCs were the only cell type to degenerate; the survival of other retinal neurons was unaffected. This retina-specific FD model is a useful in vivo model for testing potential therapeutics for mitigating blindness in FD. Moreover, our data indicate that RGCs and mitochondria are promising targets.


Assuntos
Proteínas de Transporte/metabolismo , Disautonomia Familiar/patologia , Disautonomia Familiar/fisiopatologia , Mitocôndrias/patologia , Degeneração Retiniana/patologia , Degeneração Retiniana/fisiopatologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Trifosfato de Adenosina/metabolismo , Animais , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intracelular , Potencial da Membrana Mitocondrial , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/ultraestrutura , Especificidade de Órgãos , Células Ganglionares da Retina/ultraestrutura
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