6 documents found, page 1 of 1
Cholesterol redistribution triggered by CYP46A1 gene therapy improves major hal...
Nunes, Maria João; Carvalho, Andreia N.; Reis, Joana; Costa, Daniela; Moutinho, Miguel; Mateus, Joana; Mendes de Almeida, Rita; Brito, SaraCholesterol 24-hydroxylase (CYP46A1) is an exclusively neuronal cytochrome P450 enzyme responsible for converting cholesterol into 24S-hydroxycholesterol, which serves as the primary pathway for eliminating cholesterol in the brain. We and others have shown that increased activity of CYP46A1 leads to reduced levels of cholesterol and has a positive effect on cognition. Therefore, we hypothesized that CYP46A1 co...
New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploi...
Guedes, Romina A.; Grilo, Jorge H.; Carvalho, Andreia N.; Fernandes, Pedro M. P.; Ressurreição, Ana S.; Brito, Vanessa; Santos, Adriana O.Cancer is a complex multifactorial disease whose pathophysiology involves multiple metabolic pathways, including the ubiquitin-proteasome system, for which several proteasome inhibitors have already been approved for clinical use. However, the resistance to existing therapies and the occurrence of severe adverse effects is still a concern. The purpose of this study was the discovery of novel scaffolds of protea...
Revisiting Proteasome Inhibitors: Molecular Underpinnings of Their Development,...
Leonardo-Sousa, Carlota; Carvalho, Andreia Neves; Guedes, Romina A.; Fernandes, Pedro M. P.; Aniceto, Natália; Salvador, Jorge A. R.; Gama, Maria JoãoProteasome inhibitors have shown relevant clinical activity in several hematological malignancies, namely in multiple myeloma and mantle cell lymphoma, improving patient outcomes such as survival and quality of life, when compared with other therapies. However, initial response to the therapy is a challenge as most patients show an innate resistance to proteasome inhibitors, and those that respond to the therap...
Neurotoxic effects of MPTP on mouse cerebral cortex: Modulation of neuroinflamm...
Mendes, Mariana Oliveira; Rosa, Alexandra Isabel; Carvalho, Andreia Neves; Nunes, Maria João; Dionísio, Pedro; Rodrigues, Elsa; Costa, DanielaParkinson's disease (PD) is a progressive neurological disorder, mainly characterized by the progressive loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc) and by the presence of intracellular inclusions, known as Lewy bodies. Despite SNpc being considered the primary affected region in PD, the neuropathological features are confined solely to the nigro-striatal axis. With disease progres...
Tauroursodeoxycholic Acid Improves Motor Symptoms in a Mouse Model of Parkinson...
Rosa, Alexandra Isabel; Silva, Sara Carina Duarte; Silva-Fernandes, Anabela; Nunes, Maria João; Carvalho, Andreia Neves; Rodrigues, ElsaParkinson's disease (PD) is characterized by severe motor symptoms, and currently there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Tauroursodeoxycholic acid (TUDCA) is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD; however, its effect in PD motor symptoms has never been addressed. In the present work...
Cholesterol 24S-Hydroxylase overexpression inhibits the liver X receptor (LXR) ...
Moutinho, Miguel; Nunes, Maria João; Gomes, Anita Q.; Gama, Maria João; Cedazo-Minguez, Angel; Rodrigues, C. M.; Björkhem, Ingemar; Rodrigues, ElsaThe neuronal-specific cholesterol 24S-hydroxylase (CYP46A1) is important for brain cholesterol elimination. Cyp46a1 null mice exhibit severe deficiencies in learning and hippocampal long-term potentiation, suggested to be caused by a decrease in isoprenoid intermediates of the mevalonate pathway. Conversely, transgenic mice overexpressing CYP46A1 show an improved cognitive function. These results raised the que...