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1.
Int J Mol Sci ; 21(9)2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32392803

RESUMO

Oxysterols, important regulators of cholesterol homeostasis in the brain, are affected by neurodegenerative diseases. Early-onset Alzheimer's disease is associated with higher levels of circulating brain-derived 24S-hydroxycholesterol (24S-OHC). Conversion of cholesterol to 24S-OHC is mediated by cholesterol 24S-hydroxylase in the brain, which is the major pathway for oxysterol elimination, followed by oxidation through hepatic first-pass metabolism by CYP39A1. Abnormal CYP39A1 expression results in accumulation of 24S-OHC, influencing neurodegenerative disease-related deterioration; thus, it is important to understand the normal elimination of 24S-OHC and the system regulating CYP39A1, a selective hepatic metabolic enzyme of 24S-OHC. We examined the role of transcriptional regulation by retinoic acid receptor-related orphan receptor α (RORα), a nuclear receptor that responds to oxysterol ligands. In humans, the promoter and first intronic regions of CYP39A1 contain two putative RORα response elements (ROREs). RORα binding and responses of these ROREs were assessed using electrophoretic mobility shift, chromatin immunoprecipitation, and luciferase reporter assays. CYP39A1 was upregulated by RORα overexpression in HEK293 cells, while RORα knockdown by siRNA significantly downregulated CYP39A1 expression in human hepatoma cells. Additionally, CYP39A1 was induced by RORα agonist treatment, suggesting that CYP39A1 expression is activated by RORα nuclear receptors. This may provide a way to increase CYP39A1 activity using RORα agonists, and help halt 24S-OHC accumulation in neurodegenerative illnesses.


Assuntos
Encéfalo/metabolismo , Hidroxicolesteróis/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Esteroide Hidroxilases/genética , Regulação da Expressão Gênica , Células HEK293 , Células Hep G2 , Humanos , Hidroxicolesteróis/sangue , Íntrons , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Elementos de Resposta , Esteroide Hidroxilases/química , Esteroide Hidroxilases/metabolismo
2.
Intern Med ; 54(17): 2207-11, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26328648

RESUMO

A 29-year-old woman was diagnosed with Henoch-Schönlein purpura nephritis (HSPN) based on the presence of purpura and histopathological findings showing crescent formation, mesangial proliferation and IgA deposition in the glomerular mesangium. She was treated with high-dose steroids; however, the nephritic syndrome persisted. Therefore, we diagnosed her with steroid-resistant HSPN and decided to add treatment with cyclosphamide pulse therapy. After one year of treatment, the histopathological findings, including crescent formation and IgA deposition, improved, as confirmed on a renal biopsy, and the patient fulfilled the criteria for complete remission. Cyclophosphamide pulse therapy may be considered an effective treatment for intractable HSPN.


Assuntos
Ciclofosfamida/administração & dosagem , Vasculite por IgA/tratamento farmacológico , Imunossupressores/administração & dosagem , Nefrite/patologia , Pulsoterapia , Esteroides/administração & dosagem , Adulto , Ciclofosfamida/efeitos adversos , Feminino , Frequência Cardíaca , Humanos , Vasculite por IgA/patologia , Imunossupressores/efeitos adversos , Monitorização Fisiológica , Nefrite/imunologia , Indução de Remissão , Resultado do Tratamento
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