A5057925009- Cancer-related Molecular Pathways
- Ubiquitin and proteasome pathways
- Parkinson's Disease Mechanisms and Treatments
- Cellular transport and secretion
- Lysosomal Storage Disorders Research
- Cancer, Hypoxia, and Metabolism
- Cancer therapeutics and mechanisms
- Synthesis and pharmacology of benzodiazepine derivatives
- Healthcare Quality and Management
- Growth Hormone and Insulin-like Growth Factors
- Gastrointestinal Bleeding Diagnosis and Treatment
- CRISPR and Genetic Engineering
- Children's Physical and Motor Development
- Cancer Research and Treatments
- Calcium signaling and nucleotide metabolism
- Epigenetics and DNA Methylation
- Skin and Cellular Biology Research
- RNA modifications and cancer
- Thyroid Disorders and Treatments
- Neuroblastoma Research and Treatments
- Inclusion and Disability in Education and Sport
- PARP inhibition in cancer therapy
- Traditional Chinese Medicine Analysis
- Click Chemistry and Applications
- Neuroscience of respiration and sleep
MRC Protein Phosphorylation and Ubiquitylation Unit
2021-2024
University of Dundee
2021-2024
Medical Research Council
2021-2024
Instituto Politécnico de Leiria
2023-2024
University of Minho
2023
Clinical Academic Center of Braga
2023
Universidade de Sorocaba
2022
University of Trás-os-Montes and Alto Douro
2022
Universidade do Porto
2013-2019
Rede de Química e Tecnologia
2013-2019
Abstract Heterozygous gain-of-kinase function variants in LRRK2 (leucine-rich repeat kinase 2) cause 1–2% of all cases Parkinson’s disease (PD) albeit with incomplete and age-dependent penetrance. All pathogenic mutations reside within the two catalytic domains LRRK2—either its domain (e.g. G2019S) modest effect or ROC-COR GTPase R1441G/H) large on activity. We have previously reported assays to interrogate pathway activity human bio-samples measuring phosphorylation endogenous substrate...
Abstract Elevated urine bis(monoacylglycerol)phosphate (BMP) levels have been found in gain-of-kinase function LRRK2 G2019S mutation carriers. Here, we expanded BMP analysis to other Parkinson’s disease (PD) associated mutations and them be consistently elevated carriers of R1441G/C as well VPS35 D620N mutations. Urine are promising biomarkers for patient stratification potentially target engagement clinical trials emerging targeted PD therapies.
Abstract Lysosomes are implicated in a wide spectrum of human diseases including monogenic lysosomal storage disorders (LSDs), age-associated neurodegeneration and cancer. Profiling content using tag-based immunoprecipitation (LysoTagIP) cell animal models allowed major discoveries the field, however studying dysfunction patients remains challenging. Here, we report development “tagless LysoIP method” to enable rapid enrichment lysosomes, via immunoprecipitation, endogenous integral membrane...
Bis(monoacylglycero)phosphate (BMP), a distinct anionic phospholipid predominantly found in late endosomes and lysosomes, plays pivotal role supporting lysosomal functions maintaining metabolic homeostasis. Its impaired function is associated with an array of disorders, notably neurodegenerative diseases. However, the identification quantitation BMP remains difficult due to its structural similarity isomer phosphatidylglycerol (PG), thus necessitating robust analytical methods for accurate...
// Joana Soares 1, 2 , Liliana Raimundo Nuno A.L. Pereira 4 Ângelo Monteiro Sara Gomes Cláudia Bessa Clara Glória Queiroz 3 Alessandra Bisio 5 João Fernandes 6 Célia Flávio Reis Jorge Gonçalves Alberto Inga Maria M.M. Santos Lucília Saraiva 1 UCIBIO/REQUIMTE, Universidade do Porto, Portugal Laboratório de Microbiologia, Departamento Ciências Biológicas, Faculdade Farmácia, Farmacologia, Medicamento, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Lisboa, CIBIO, Centre...
α-Mangostin (1) and gambogic acid (2) are natural products with potent cytotoxic activity against several human tumor cells. However, their molecular mechanisms of action remain controversial. In this work, using yeast-based assays, it was shown that both xanthones potential inhibitors the p53–MDM2 interaction. This on interaction confirmed by a gene reporter assay in cell. Additionally, computational docking studies supported these to bind MDM2 therefore act as putative inhibitors....
The transcription factor p53 plays a crucial role in cancer development and dissemination, thus, p53-targeted therapies are among the most encouraging anticancer strategies. In human cancers with wild-type (wt) p53, its inactivation by interaction murine double minute (MDM)2 MDMX is common event. Simultaneous inhibition of both MDMs to restore tumor suppressor activity p53. Here, we describe synthesis new tryptophanol-derived oxazoloisoindolinone DIMP53-1 identify as dual inhibitor...
The virtual screening of a library chalcone derivatives led us to the identification potential new MDM2 ligands. chalcones with best docking scores obeying Lipinski rule five were subsequently prepared by base-catalyzed aldol reactions. activity these compounds as inhibitors p53–MDM2 interaction was investigated using yeast-based assay. Using this approach two (3 and 4) identified putative small molecule interaction. both further in panel human tumor cells. Chalcones 3 4 revealed pronounced...
Half of human cancers harbor TP53 mutations that render p53 inactive as a tumor suppressor. In these cancers, reactivation mutant (mutp53) through restoration wild-type-like function constitutes valuable anticancer therapeutic strategy. order to search for mutp53 reactivators, small library tryptophanol-derived oxazoloisoindolinones was synthesized and the potential compounds reactivators agents investigated in cells xenograft mouse models. By analysis their anti-proliferative effect on...
The p53 tumor suppressor is widely found to be mutated in human cancer. This protein regarded as a molecular hub regulating different cell responses, namely death. Compelling data have demonstrated that the impairment of activity correlates with development and maintenance. For these reasons, reactivation function promising strategy halt In present work, recombinant mutant p53R280K DNA binding domain (DBD) was produced for first time, its crystal structure determined absence resolution 2.0...
Yeast has proven to be an efficient model system for functional and pharmacological studies of the p53 tumour suppressor protein. In this work, human p53-MDMX regulatory pathway was reconstituted in yeast. Additionally, by using known inhibitor interaction, SJ-172550, efficacy a simplified yeast-based screening assay search inhibitors interaction is demonstrated first time. Moreover, further insights on transcriptional activity yeast are provided. particular, it shown that reported wild-type...
The ubiquitous nitrite is a major analyte in the management of human health and environmental risks. current analytical methods are complex techniques that do not fulfil need for simple, robust low-cost tools on-site monitoring. Electrochemical reductase-based biosensors presented as powerful alternative, due to their good performance miniaturization potential. However, real-world application limited by anoxic working conditions, standard oxygen removal strategies incompatible with...
The finding that the well-known mammalian P53 protein can act as a transcription factor (TF) in yeast S. cerevisiae has allowed for development of different functional assays to study impacts 1) binding site [i.e., response element (RE)] sequence variants on transactivation specificity or 2) TP53 mutations, co-expressed cofactors, small molecules activity. Different basic and translational research applications have been developed. Experimentally, these approaches exploit two major...
Pregnancy places a metabolic overload on the maternal thyroid, especially in first trimester, mainly because of demand imposed by conceptus. The fetal thyroid becomes functionally mature only around pregnancy week 20. Until then, fetus depends transfer hormones (THs).
Lysosomes are implicated in a wide spectrum of human diseases including monogenic lysosomal storage disorders (LSDs), age-associated neurodegeneration and cancer. Profiling content using tag-based immunoprecipitation (LysoTagIP) cell animal models has substantially moved the field forward, but studying dysfunction patients remains challenging. Here, we report development 'tagless LysoIP' method, designed to enable rapid enrichment lysosomes, via immunoprecipitation, endogenous integral...
Capsule endoscopy is becoming the major medical technique for examination of gastrointestinal tract, and detection small bowel lesions. With growth endoscopic capsules lack an appropriate tracking system to allow localization lesions, need develop software-based techniques localisation capsule at any given frame also increasing. this in mind, knowing availability labelled datasets, work aims a unsupervised method homography estimation video frames, later be applied systems. The pipeline...
Wireless capsule endoscopy is a relatively novel technique used for imaging of the gastrointestinal tract. Unlike traditional approaches, it allows painless visualisation whole tract, including small bowel, region difficult access. Endoscopic capsules record about 8h, producing around 60,000 images. These are analysed by an expert that identifies abnormalities present in frames, process very tedious and prone to errors. Thus there clear need develop systems automatically analyse this data...
Accreditation processes for health care professions are designed to ensure that individuals and programs in these fields meet established standards of quality effectiveness. The accelerating pace globalization the has increased need a shared understanding vocabulary evaluation, assessment, accreditation. psychometric principles valid reliable assessment commonly accepted, but terminology is confusing. We believe all stakeholders - evaluators, faculty, students also community will benefit...
Among natural chemicals used as cancer chemo-preventive and/or chemotherapeutic agents, saponins represent one of the most promising and interesting family compounds. In this work, we aimed to elucidate biological effects on human cells six saponin fractions (SFs) obtained from in vitro cultures Astragalus verrucosus Moris, a poorly characterized species. Interestingly, SF (3) showed strongly inhibitory effect proliferation colon adenocarcinoma cell line (HCT116) via activation p53-dependent...