The DTB group is deeply committed to the elucidation of the underlying causes and mechanisms of health, aging and disease, as well as to the identification of biomarkers and discovery of new therapeutic targets/drugs. Pursuing our main goals, our research focus on: i) Cannabinoids, as biomarkers and therapeutic drugs, in reproduction/infertility and cancer; ii) New inflammatory and oxidative stress markers as predictors of human oocyte quality; iii) Acquired resistance mechanisms to aromatase inhibitors and new targets/drugs to improve ER+ breast cancer therapy; iv) Identification of biomarkers of renal damage, progression and mortality prediction, to enhance information on chronic kidney disease (CDK) and in the regulation of erythropoietin gene expression in CKD anemia; v) Improvement of biocompatibility of hemodialysis membranes; vi) Evaluate the impact of interventions to improve adherence and prevent / mitigate fragility and develop tools to evaluate the implementation of technological solutions in the elderly.
Hormone dependent breast cancer: autophagy and PI3K in exemestane-acquired resistance and new potential aromatase inhibitors
Exemestane is a third-generation steroidal aromatase inhibitor (AI) used for the ER+ breast cancer treatment. Despite its therapeutic success, exemestane-acquired resistance may occur leading to tumor relapse. We showed that exemestane induces autophagy as a cytoprotective mechanism linked to acquired resistance, and that inhibition of autophagy and/or PI3K pathway reverts Exemestane-resistance, by promoting apoptosis. In addition, new 7alpha-substituted steroidal molecules showed to be potent AIs and have anti-tumor efficacy in breast cancer cells. Therefore, it is highlighted not only new targets that together with aromatase inhibition may improve breast cancer therapy, overcoming AIs acquired resistance, but also the structural modifications in steroidal scaffold that are translated into better aromatase inhibition and anti-tumor properties, providing important information for the rational design/synthesis of more effective AIs.
Autophagy as a mechanism of exemestane acquired resistance
DNA damage in end-stage renal disease patients. Assessment by in vitro comet assay and by cell-free DNA quantification
Our studies showed that cell damaged DNA is increased in ESRD patients, and suggest that at lower C-reactive protein (CRP) values the damaged DNA remains within the cell, while at higher CRP values damaged DNA is released into plasma and may contribute to further enhance inflammation in ESRD patients and increase mortality risk. ESRD patients who had died within one year follow-up period of the study, presented higher circulating damaged DNA and inflammation. Our data suggest that the comet assay is more sensitive for low grade inflammatory conditions, while cell free DNA appears as a good biomarker for more severe inflammatory conditions, as well as a biomarker for the outcome of ESRD patients.
Comet images of lymphocytes from endstage renal disease (ERSD) patients showing the different migration patterns according to the levels of DNA damage, from class 0 (undamaged) to class 4 (severe damage).
- “The endocannabinoids as modulators of cell death and differentiation: A unified hypothesis of how cannabinoids affect placental development”, FCT-MCTES and FEDER, Total and Unit funding €102,455, Georgina Correia da Silva (PI).
- “DESignBIOtecHealth: new technologies for three health challenges of modern societies: diabetes, drugs abuse and kidney diseases”, FEDER-Portugal 2020, Total funding: €2.8M, Unit funding: €374,000, Alice Silva (PI of the sub-area NEPHROCARDIORISK).
- “ADErIR Study - Together We Stand: Promoting adherence in end-stage renal disease through a family based selfmanagement intervention”, FCT-MCTES, Total funding: €211,100, Unit funding: €3,750.
- “Emerging inflammatory mediators as predictors of oocyte quality and assisted reproduction techniques outcome: from biochemical markers to clinic”, FCTMCTES, Total funding: €239,420, Unit funding: €211,700, Irene Rebelo (PI).
Borges, M; Silva, TM; Brito, C; Teixeira, N; Roberts, CW. 2019. How does toxoplasmosis affect the maternal-foetal immune interface and pregnancy?. PARASITE IMMUNOLOGY, 41, DOI: 10.1111/pim.12606
Kohlova, M; Amorim, CG; Araujo, A; Santos-Silva, A; Solich, P; Montenegro, MCBSM. 2019. The biocompatibility and bioactivity of hemodialysis membranes: their impact in end-stage renal disease. JOURNAL OF ARTIFICIAL ORGANS, 22, DOI: 10.1007/s10047-018-1059-9
Sa, SI; Maia, J; Bhowmick, N; Silva, SM; Silva, A; Correia-da-Silva, G; Teixeira, N; Fonseca, BM. 2019. Uterine histopathological changes induced by acute administration of tamoxifen and its modulation by sex steroid hormones. TOXICOLOGY AND APPLIED PHARMACOLOGY, 363, DOI: 10.1016/j.taap.2018.11.015
Fonseca, BM; Fernandes, R; Almada, M; Santos, M; Carvalho, F; Teixeira, NA; Correia-da-Silva, G. 2019. Synthetic cannabinoids and endometrial stromal cell fate: Dissimilar effects of JWH-122, UR-144 and WIN55,212-2. TOXICOLOGY, 413, DOI: 10.1016/j.tox.2018.11.006
Roleira, FMF; Varela, C; Amaral, C; Costa, SC; Correia-da-Silva, G; Moraca, F; Costa, G; Alcaro, S; Teixeira, NAA; da Silva, EJT. 2019. C-6 alpha- vs C-7 alpha-Substituted Steroidal Aromatase Inhibitors: Which Is Better? Synthesis, Biochemical Evaluation, Docking Studies, and Structure-Activity Relationships. JOURNAL OF MEDICINAL CHEMISTRY, 62, DOI: 10.1021/acs.jmedchem.9b00157