Cytotoxic activity and mechanism of action of organometallic complexes

Tese de mestrado, Bioquímica (Bioquímica Médica), Universidade de Lisboa, Faculdade de Ciências, 201

NF-κB and HIF crosstalk in immune responses

Hypoxia and inflammation have been associated with a number of pathological conditions, in particular inflammatory diseases. While hypoxia is mainly associated with the activation of hypoxia‐inducible factors (HIFs), inflammation activates the family of transcription factor called nuclear factor‐kappa B (NF‐κB). An extensive crosstalk between these two main molecular players involved in hypoxia and inflammation has been demonstrated. This crosstalk includes common activating stimuli, shared regulators and targets. In this review, we discuss the current understanding of the role of NF‐κB and HIF in the context of the immune response. We review the crosstalk between HIF and NF‐κB in the control of the immune response in different immune cell types including macrophages, neutrophils and B and T cells. Furthermore the importance of the molecular crosstalk between HIFs and NF‐κB for a variety of medical conditions will be discussed

PITX1, a specificity determinant in the HIF-1α-mediated transcriptional response to hypoxia

Hypoxia is an important developmental cue for multicellular organisms but it is also a contributing factor for several human pathologies, such as stroke, cardiovascular diseases and cancer. In cells, hypoxia activates a major transcriptional program coordinated by the Hypoxia Inducible Factor (HIF) family. HIF can activate more than one hundred targets but not all of them are activated at the same time, and there is considerable cell type variability. In this report we identified the paired-like homeodomain pituitary transcription factor (PITX1), as a transcription factor that helps promote specificity in HIF-1α dependent target gene activation. Mechanistically, PITX1 associates with HIF-1β and it is important for the induction of certain HIF-1 dependent genes but not all. In particular, PITX1 controls the HIF-1α-dependent expression of the histone demethylases; JMJD2B, JMJD2A, JMJD2C and JMJD1B. Functionally, PITX1 is required for the survival and proliferation responses in hypoxia, as PITX1 depleted cells have higher levels of apoptotic markers and reduced proliferation. Overall, our study identified PITX1 as a key specificity factor in HIF-1α dependent responses, suggesting PITX1 as a protein to target in hypoxic cancers

Hypoxia activates IKK-NF-κB and the immune response in <em>Drosophila melanogaster</em>

Hypoxia, or low oxygen availability, is an important physiological and pathological stimulus for multicellular organisms. Molecularly, hypoxia activates a transcriptional programme directed at restoration of oxygen homoeostasis and cellular survival. In mammalian cells, hypoxia not only activates the HIF (hypoxia-inducible factor) family, but also additional transcription factors such as NF-κB (nuclear factor κB). Here we show that hypoxia activates the IKK–NF-κB [IκB (inhibitor of nuclear factor κB)–NF-κB] pathway and the immune response in Drosophila melanogaster. We show that NF-κB activation is required for organism survival in hypoxia. Finally, we identify a role for the tumour suppressor Cyld, as a negative regulator of NF-κB in response to hypoxia in Drosophila. The results indicate that hypoxia activation of the IKK–NF-κB pathway and the immune response is an important and evolutionary conserved response

SINHCAF/FAM60A and SIN3A specifically repress HIF 2α expression

The SIN3A–HDAC (histone deacetylase) complex is a master transcriptional repressor, required for development but often deregulated in disease. Here, we report that the recently identified new component of this complex, SINHCAF (SIN3A and HDAC-associated factor)/FAM60A (family of homology 60A), links the SIN3A–HDAC co-repressor complex function to the hypoxia response. We show that SINHCAF specifically represses HIF-2α mRNA and protein expression, via its interaction with the transcription factor SP1 (specificity protein 1) and recruitment of HDAC1 to the HIF-2α promoter. SINHCAF control over HIF-2α results in functional cellular changes in in vitro angiogenesis and viability. Our analysis reveals an unexpected link between SINHCAF and the regulation of the hypoxia response

Mo(II) complexes: A new family of cytotoxic agents?

respectively. These results suggest that they interact with DNA changing its conformation and possibly inducing cell death, and may therefore provide a valuable tool in cancer chemotherapy

Quantitative risk-benefit assessment of Portuguese fish and other seafood species consumption scenarios

Portugal has high fish/seafood consumption, which may have both risks and benefits. This study aims to quantify the net health impact of hypothetical scenarios of fish/seafood consumption in the Portuguese population using a risk-benefit assessment methodology. Consumption data from the National Food, Nutrition and Physical Activity Survey 2015-2016 (n 5811) were used to estimate the mean exposure to methylmercury and EPA + DHA in the current and the alternative scenarios considered. Alternative scenarios (alt) were modelled using probabilistic approaches to reflect substitutions from the current consumption in the type of fish/seafood (alt1: excluding predatory fishes; alt2: including only methylmercury low-level fishes) or in the frequency of weekly fish/seafood consumption (alt3 to alt6: 1, 3, 5 or 7 times a week, replacing fish/seafood meals with meat or others). The overall health impact of these scenarios was quantified using disability-adjusted life years (DALY). In the Portuguese population, about 11 450 DALY could be prevented each year if the fish/seafood consumption increased to a daily basis. However, such a scenario would result in 1398 extra DALY considering the consumption by pregnant women and the respective risk on fetal neurodevelopment. Our findings support a recommendation to increase fish/seafood consumption up to 7 times/week. However, for pregnant women and children, special considerations must be proposed to avoid potential risks on fetal neurodevelopment due to methylmercury exposure.This work was supported by the EEA Grants Program, Public Health Initiatives (PT06 – 000088SI3); the Operational Programme Factors of Competitiveness – COMPETE from FEDER and national funding from the Foundation for Science and Technology – FCT (Portuguese Ministry of Education and Science) under the project ‘FOCAcCIa’ (POCI-01–0145-FEDER031949); the Epidemiology Research Unit (UIDB/04750/2020) (POCI-01–0145-FEDER-006862) and the FCT doctoral grant (SFRH/BD/146078/2019) (CC).info:eu-repo/semantics/publishedVersio