Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Más filtros

Banco de datos
Tipo del documento
País de afiliación
Intervalo de año de publicación
1.
Nucleic Acids Res ; 51(7): 3150-3165, 2023 04 24.
Artículo en Inglés | MEDLINE | ID: mdl-36869674

RESUMEN

DNA double-strand breaks (DSBs) are functionally linked to genomic instability in spermatocytes and to male infertility. The heavy metal cadmium (Cd) is known to induce DNA damage in spermatocytes by unknown mechanisms. Here, we showed that Cd ions impaired the canonical non-homologous end-joining (NHEJ) repair pathway, but not the homologous recombination (HR) repair pathway, through stimulation of Ser2056 and Thr2609 phosphorylation of DNA-PKcs at DSB sites. Hyper-phosphorylation of DNA-PKcs led to its premature dissociation from DNA ends and the Ku complex, preventing recruitment of processing enzymes and further ligation of DNA ends. Specifically, this cascade was initiated by the loss of PP5 phosphatase activity, which results from the dissociation of PP5 from its activating ions (Mn), that is antagonized by Cd ions through a competitive mechanism. In accordance, in a mouse model Cd-induced genomic instability and consequential male reproductive dysfunction were effectively reversed by a high dosage of Mn ions. Together, our findings corroborate a protein phosphorylation-mediated genomic instability pathway in spermatocytes that is triggered by exchange of heavy metal ions.


Asunto(s)
Cadmio , Inestabilidad Genómica , Infertilidad Masculina , Espermatocitos , Animales , Humanos , Masculino , Ratones , Cadmio/toxicidad , ADN/metabolismo , Reparación del ADN por Unión de Extremidades , Reparación del ADN , Inestabilidad Genómica/efectos de los fármacos , Infertilidad Masculina/genética , Infertilidad Masculina/metabolismo , Iones/metabolismo , Fosforilación , Reparación del ADN por Recombinación , Espermatocitos/efectos de los fármacos
2.
Neurochem Int ; 62(3): 340-7, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23318673

RESUMEN

Although the pathogenesis of sporadic Alzheimer's disease (AD) is not clearly understood, neuroinflammation has been known to play a role in the pathogenesis of AD. To investigate a functional link between the neuroinflammation and AD, the effect of leukotriene D4 (LTD4), an inflammatory lipid mediator, was studied on amyloid-ß generation in vitro. Application of LTD4 to cell monolayers at concentrations up to 40 nM LTD4 caused increases in the Aß releases. Concentrations ≥ 40 nM LTD4 decreased neuronal viability. Application of 20 nM LTD4 caused a significant increase in Aß generation, as assessed by ELISA or Western blotting, without significant cytotoxicity. At this concentration, exposure of neurons to LTD4 for 24h produced maximal effect in the Aß generation, and significant increases in the expressions of cysteinyl leukotriene 1 receptor (CysLT(1)R) and activity of ß- or γ-secretase with complete abrogation by the selective CysLT(1)R antagonist pranlukast. Exposure of neurons to LTD4 for 1h showed activation of NF-κB pathway, by assessing the levels of p65 or phospho-p65 in the nucleus, and either CysLT(1)R antagonist pranlukast or NF-κB inhibitor PDTC prevented the nuclear translocation of p65 and the consequent phosphorylation. PDTC also inhibited LTD4-induced elevations of ß- or γ-secretase activity and Aß generation in vitro. Overall, our data show for the first time that LTD4 causes Aß production by enhancement of ß- or γ-secretase resulting from activation of CysLT(1)R-mediated NF-κB signaling pathway. These findings provide a novel pathologic link between neuroinflammation and AD.


Asunto(s)
Péptidos beta-Amiloides/biosíntesis , Leucotrieno D4/farmacología , FN-kappa B/metabolismo , Neuronas/metabolismo , Receptores de Leucotrienos/fisiología , Animales , Secuencia de Bases , Western Blotting , Cartilla de ADN , Ensayo de Inmunoadsorción Enzimática , Ratones , Ratones Endogámicos ICR , Reacción en Cadena de la Polimerasa
3.
CNS Neurosci Ther ; 18(8): 659-66, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22620268

RESUMEN

AIMS: Pioglitazone, known as a peroxisome proliferator-activated receptor γ (PPARγ) agonist, is used to treat type 2 diabetes mellitus (T2DM). T2DM has been associated with reduced performance on numerous domains of cognitive function. Here, we investigated the effects of pioglitazone on memory impairment in a mouse model with defects in insulin sensitivity and secretion, namely high-fat diet (HFD) streptozotocin (STZ)-induced diabetic mice. METHODS: ICR mice were fed with HFD for 4 weeks and then injected with a single low dose of STZ followed by continued HFD feeding for an additional 4 weeks. Pioglitazone (18 mg/kg, 9 mg/kg body weight) was orally administered for 6 weeks once daily. Y-maze test and Morris water maze test (MWM) were employed for testing learning and memory. Serum glucose, serum insulin, serum triglyceride, brain ß-amyloid peptide (Aß), brain ß-site amyloid precursor protein cleaving enzyme (BACE1), brain nuclear factor κB (NF-κB), and brain receptor for advanced glycation end products (RAGE) were also tested. RESULTS: The STZ/HFD diabetic mice, characterized by hyperglycemia, hyperlipemia and hypoinsulinemia, performed poorly on Y-maze and MWM hence reflecting impairment of learning and memory behavior with increases of Aß40/Aß42, BACE1, NF-κB, and RAGE in brain. Treatment of PPARγ agonist, pioglitazone (18 or 9 mg/kg body weight), significantly reversed diabetes-induced impairment of learning and memory behavior, which is involved in decreases of Aß40/Aß42 via inhibition of NF-κB, BACE1 and RAGE in brain as well as attenuation of hyperglycemia, hyperlipemia, and hypoinsulinemia. CONCLUSIONS: It is concluded that PPARγ agonist pioglitazone may be considered as potential pharmacological agents for the management of cognitive dysfunction in T2DM.


Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/psicología , Hipoglucemiantes/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/etiología , PPAR gamma/agonistas , Tiazolidinedionas/uso terapéutico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Conducta Animal/efectos de los fármacos , Glucemia/metabolismo , Western Blotting , Química Encefálica/efectos de los fármacos , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/psicología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/psicología , Ensayo de Inmunoadsorción Enzimática , Productos Finales de Glicación Avanzada/metabolismo , Inmunohistoquímica , Insulina/sangre , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos ICR , FN-kappa B/metabolismo , Pioglitazona , Triglicéridos/sangre
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA