Cecília Santos - Academia.edu (original) (raw)

Papers by Cecília Santos

Journal of Physiology and Biochemistry

Drug efficacy is dependent on the pharmacokinetics and pharmacodynamics of therapeutic agents. Ti... more Drug efficacy is dependent on the pharmacokinetics and pharmacodynamics of therapeutic agents. Tight junctions, detoxification enzymes, and drug transporters, due to their localization on epithelial barriers, modulate the absorption, distribution, and the elimination of a drug. The epithelial barriers which control the pharmacokinetic processes are sex steroid hormone targets, and in this way, sex hormones may also control the drug transport across these barriers. Thus, sex steroids contribute to sex differences in drug resistance and have a relevant impact on the sex-related efficacy of many therapeutic drugs. As a consequence, for the further development and optimization of therapeutic strategies, the sex of the individuals must be taken into consideration. Here, we gather and discuss the evidence about the regulation of ATP-binding cassette transporters by sex steroids, and we also describe the signaling pathways by which sex steroids modulate ATP-binding cassette transporters ex...

Pharmaceutics

Despite the great progress over the past few decades in both the diagnosis and treatment of a gre... more Despite the great progress over the past few decades in both the diagnosis and treatment of a great variety of human cancers, glioblastoma remains the most lethal brain tumor. In recent years, cancer gene therapy focused on non-viral vectors which emerged as a promising approach to glioblastoma treatment. Transferrin (Tf) easily penetrates brain cells of the blood–brain barrier, and its receptor is highly expressed in this barrier and glioblastoma cells. Therefore, the development of delivery systems containing Tf appears as a reliable strategy to improve their brain cells targeting ability and cellular uptake. In this work, a cell-penetrating peptide (WRAP5), bearing a Tf-targeting sequence, has been exploited to condense tumor suppressor p53-encoding plasmid DNA (pDNA) for the development of nanocomplexes. To increase the functionality of developed nanocomplexes, the drug Temozolomide (TMZ) was also incorporated into the formulations. The physicochemical properties of peptide/pDNA...

International Journal of Molecular Sciences, 2022

The choroid plexuses (CPs), located in the brain ventricles, form an interface between the blood ... more The choroid plexuses (CPs), located in the brain ventricles, form an interface between the blood and the cerebrospinal fluid named the blood-cerebrospinal barrier, which, by the presence of tight junctions, detoxification enzymes, and membrane transporters, limits the traffic of molecules into the central nervous system. It has already been shown that sex hormones regulate several CP functions, including the oscillations of its clock genes. However, it is less explored how the circadian rhythm regulates CP functions. This study aimed to evaluate the impact of sex hormones and circadian rhythms on the function of CP membrane transporters. The 24 h transcription profiles of the membrane transporters rAbca1, rAbcb1, rAbcc1, rAbcc4, rAbcg2, rAbcg4, and rOat3 were characterized in the CPs of intact male, intact female, sham-operated female, and gonadectomized rats. We found that rAbcc1 is expressed in a circadian way in the CPs of intact male rats, rAbcg2 in the CPs of intact female rats...

Life, 2021

The Six Transmembrane Epithelial Antigen of the Prostate (STEAP1) is an oncogene overexpressed in... more The Six Transmembrane Epithelial Antigen of the Prostate (STEAP1) is an oncogene overexpressed in several human tumors, particularly in prostate cancer (PCa). However, the mechanisms involved in its overexpression remain unknown. It is well known that epigenetic modifications may result in abnormal gene expression patterns, contributing to tumor initiation and progression. Therefore, this study aimed to analyze the methylation pattern of the STEAP1 gene in PCa versus non-neoplastic cells. Bisulfite amplicon sequencing of the CpG island at the STEAP1 gene promoter showed a higher methylation level in non-neoplastic PNT1A prostate cells than in human PCa samples. Bioinformatic analysis of the GEO datasets also showed the STEAP1 gene promoter as being demethylated in human PCa, and a negative association with STEAP1 mRNA expression was observed. These results are supported by the treatment of non-neoplastic PNT1A cells with DNMT and HDAC inhibitors, which induced a significant increase...

Neuroendocrinology, 2021

Melatonin, an indolamine mainly released from the pineal gland, is associated with many biologica... more Melatonin, an indolamine mainly released from the pineal gland, is associated with many biological functions, namely, the modulation of circadian and seasonal rhythms, sleep inducer, regulator of energy metabolism, antioxidant, and anticarcinogenic. Although several pieces of evidence also recognize the influence of melatonin in the reproductive physiology, the crosstalk between melatonin and sex hormones is not clear. Here, we review the effects of sex differences in the circulating levels of melatonin and update the current knowledge on the link between sex hormones and melatonin. Furthermore, we explore the effects of melatonin on gonadal steroidogenesis and hormonal control in females. The literature review shows that despite the strong evidence that sex differences impact on the circadian profiles of melatonin, reports are still considerably ambiguous, and these differences may arise from several factors, like the use of contraceptive pills, hormonal status, and sleep deprivati...

Journal of Neurochemistry, 2019

In resting conditions brain adenosine concentrations are in nanomolar range, but can reach microm... more In resting conditions brain adenosine concentrations are in nanomolar range, but can reach micromolar concentrations in stressful situations such as stroke, neurodegenerative diseases or hypoxic regions of brain tumours. Adenosine usually produces its cellular effects by activating surface receptors but can also act by reversing the reaction catalysed by S-adenosylhomocysteine (SAH) hydrolase, leading to SAH accumulation and inhibition of S-adenosylmethionine (SAM)-dependent methyltransferases. Astrocytes are essential in maintaining brain homeostasis but their pathological activation and uncontrolled proliferation plays a role in neurodegeneration and glioma. Adenosine can affect cell proliferation, but the effect of increased adenosine concentration on proliferation of astrocytes is not clarified and was addressed in present work.

Journal of Neuroendocrinology, 2016

Sex hormones (SH) are essential regulators of the central nervous system. The decline in SH level... more Sex hormones (SH) are essential regulators of the central nervous system. The decline in SH levels along with ageing may contribute to compromised neuroprotection and set the grounds for neurodegeneration and cognitive impairments. In Alzheimer's disease, besides other pathological features, there is an imbalance between amyloid β (Aβ) production and clearance, leading to its accumulation in the brain of older subjects. Aβ accumulation is a primary cause for brain inflammation and degeneration, as well as concomitant cognitive decline. There is mounting evidence that SH modulate Aβ production, transport and clearance. Importantly, SH regulate most of the molecules involved in the amyloidogenic pathway, their transport across brain barriers for elimination, and their degradation in the brain interstitial fluid. This review brings together data on the regulation of Aβ production, metabolism, degradation and clearance by SH.

Neurobiology of disease, Jan 18, 2016

This article brings the choroid plexus into the context of health and disease. It is remarkable t... more This article brings the choroid plexus into the context of health and disease. It is remarkable that the choroid plexus, composed by the monolayer of epithelial cells that lie in a highly vascularized stroma, floating within the brain ventricles, gets so little attention in major physiology and medicine text books and in the scientific literature in general. Consider that it is responsible for producing most of the about 150mL of cerebrospinal fluid that fills the brain ventricles and the subarachnoid space and surrounds the spinal cord in the adult human brain, which is renewed approximately 2-3 times daily. As such, its activity influences brain metabolism and function, which will be addressed. Reflect that it contains an impressive number of receptors and transporters, both in the apical and basolateral sides of the epithelial cells, and as such is a key structure for the communication between the brain and the periphery. This will be highlighted in the context of neonatal jaundi...

The FEBS journal, May 2, 2016

The olfactory-type signaling machinery has been known to be involved not only in odorant detectio... more The olfactory-type signaling machinery has been known to be involved not only in odorant detection but also in other tissues with unsuspected sensory roles. As a barrier, the choroid plexus (CP) is an active participant in the monitoring of the cerebrospinal fluid (CSF), promptly responding to alterations in its composition. We hypothesized that olfactory signaling could be active in CP, contributing to the surveillance of the CSF composition. We found mRNA and protein expression of the major components of the olfactory transduction pathway, including odorant receptors, the olfactory G-protein (Gαolf), adenylate cyclase-3 (AC3) and the cyclic nucleotide-gated channel-2 (CNG2) in the rat CP. The functionality of the transduction pathway and the intracellular mechanisms involved were analyzed by D.C. field potential recording electrophysiological analysis, in an ex vivo CP-brain setup, using polyamines as stimuli and blockers of the downstream signaling pathways. Concentration-depende...

Alzheimer's Disease Pathogenesis-Core Concepts, Shifting Paradigms and Therapeutic Targets, 2011

Korenberg, et al. 1989), led the scientists to search AD-causing mutations in the APP gene. Since... more Korenberg, et al. 1989), led the scientists to search AD-causing mutations in the APP gene. Since that, several mutations associated with familial early onset forms of AD have been described, either in the APP gene (Kowalska 2003) or in preselin 1 (PS1) or preselin 2 (PS2) genes (Bertram et al. 2007). Either PS1 or PS2 can be the catalytic subunit of-secretase, which is the final endoprotease in the pathways that generate the A peptide (see section 2). All these findings led to the amyloid cascade hypothesis, articulated by John Hardy and others (Hardy and Higgins 1992), in which the accumulation of A peptide, generated from the proteolytic cleavage of APP in the brain, could trigger a complex downstream cascade that results in the symptoms of AD. This hypothesis states that gradual accumulation and aggregation of the hydrophobic A peptide initiates a cascade that leads to synaptic alterations, astrocytic and microglial activation, the modification of the soluble tau protein into insoluble paired helical filaments, and progressive neuronal loss associated with multiple neurotransmitter deficiencies and cognitive failure (Hardy and Selkoe 2002). The cascade hypothesis suggests that stopping or slowing formation of the A plaques would delay the onset of the disease symptoms. A is found in the extracellular fluids of the brain, including cerebrospinal fluid (CSF), and in the interstitial fluid surrounding neurons and glial cells in brain lobes (Seubert, et al. 1992; Vigo-Pelfrey, et al. 1993). Over the last years, several key proteins have been described as being implicated in A production and clearance, but further elucidation of the mechanisms involved in the process will be important for identifying new potential therapies to reduce A accumulation and combat AD. This book chapter reviews the production of A from APP and the proteins involved in its degradation and clearance. 2. Generation of amyloid beta peptides The amyloid precursor protein, APP, takes a central position in AD pathogenesis, as it is processed by the sequential action of-and-secretase, generating the A peptide, which is deposited as amyloid plaques in brains of AD individuals. APP is an integral membrane protein, with a large N-terminal extracellular domain and a short C-terminal cytoplasmatic domain, which is expressed ubiquitously in neuronal and non-neuronal cells. The human APP gene is located on chromosome 21 (Korenberg et al. 1989) and alternative splicing results in protein isoforms of various lengths: two isoforms predominant in nonneuronal tissues (751-and 770-), and the 695-amino acid form, that is the predominant isoform in neurons (Kang and Muller-Hill 1990). APP belongs to a protein family that includes APP-like protein 1 (APLP1) and 2 (APLP2) (Eggert, et al. 2004), a group of type-I transmembrane proteins that are processed in the same fashion. APP is hydrolyzed into different fragments (Figure 1) during its intracellular trafficking, and these metabolites mediate various functions (Haass 2004; Haass and Selkoe 1993). APP is first cleaved by either-or-secretase at the-or-sites, respectively, which lie in the extracellular domain of the APP. These proteases compete for APP, originating: soluble APP (sAPP , forsecretase) or soluble APP (sAPP , for-secretase), which are released to the extracellular space, and a membrane anchored C-terminal end (C83 for-secretase or C99 forsecretase). Subsequently, in the lipid bilayer,-secretase acts in the C-terminal end, C83 or C99. The-cleavage of C83 generates the APP intracellular domain (AICD), with 6kDa, and the N-terminal peptide with 3kDa (p3) into the extracellular space.-cleavage of C99, in a specific sequence (A domain) generates A peptide and the AICD. This pathway of APP processing by-secretase followed by-secretase leading to A peptide is called the www.intechopen.com

Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2011

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 ... more This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.

PLoS ONE, 2013

The choroid plexus (CP) are highly vascularized branched structures that protrude into the ventri... more The choroid plexus (CP) are highly vascularized branched structures that protrude into the ventricles of the brain, and form a unique interface between the blood and the cerebrospinal fluid (CSF), the blood-CSF barrier, that are the main site of production and secretion of CSF. Sex hormones are widely recognized as neuroprotective agents against several neurodegenerative diseases, and the presence of sex hormones cognate receptors suggest that it may be a target for these hormones. In an effort to provide further insight into the neuroprotective mechanisms triggered by sex hormones we analyzed gene expression differences in the CP of female and male rats subjected to gonadectomy, using microarray technology. In gonadectomized female and male animals, 3045 genes were differentially expressed by 1.5-fold change, compared to sham controls. Analysis of the CP transcriptome showed that the top-five pathways significantly regulated by the sex hormone background are olfactory transduction, taste transduction, metabolism, steroid hormone biosynthesis and circadian rhythm pathways. These results represent the first overview of global expression changes in CP of female and male rats induced by gonadectomy and suggest that sex hormones are implicated in pathways with central roles in CP functions and CSF homeostasis.

Molecular Cancer Research, 2012

The human 6-transmembrane epithelial antigen of prostate (STEAP) family comprises STEAP1, STEAP2,... more The human 6-transmembrane epithelial antigen of prostate (STEAP) family comprises STEAP1, STEAP2, STEAP3, and STEAP4. All of these proteins are unique to mammals and share an innate activity as metalloreductases, indicating their importance in metal metabolism. Overall, they participate in a wide range of biologic processes, such as molecular trafficking in the endocytic and exocytic pathways and control of cell proliferation and apoptosis. STEAP1 and STEAP2 are overexpressed in several types of human cancers, namely prostate, bladder, colon, pancreas, ovary, testis, breast, cervix, and Ewing sarcoma, but their clinical significance and role in cancer cells are not clear. Still, their localization in the cell membrane and differential expression in normal and cancer tissues make STEAP proteins potential candidates as biomarkers of several cancers, as well as potential targets for new immunotherapeutic strategies for disease attenuation or treatment. This review brings together the c...

Journal of Biological Chemistry, 2004

Transthyretin (TTR) is an extracellular transport protein involved in the distribution of thyroid... more Transthyretin (TTR) is an extracellular transport protein involved in the distribution of thyroid hormones and vitamin A. So far, TTR has only been found in vertebrates, of which piscine TTR displays the lowest sequence identity with human TTR (47%). Human and piscine TTR bind both thyroid hormones 3,5,3-triiodo-L-thyronine (T 3) and 3,5,3,5-tetraiodo-L-thyronine (thyroxine, T 4). Human TTR has higher affinity for T 4 than T 3 , whereas the reverse holds for piscine TTR. X-ray structures of Sparus aurata (sea bream) TTR have been determined as the apo-protein at 1.75 Å resolution and bound to ligands T 3 and T 4 , both at 1.9 Å resolution. The apo structure is similar to human TTR with structural changes only at ␤-strand D. This strand forms an extended loop conformation similar to the one in chicken TTR. The piscine TTR⅐T 4 complex shows the T 4-binding site to be similar but not identical to human TTR, whereas the TTR⅐T 3 complex shows the I3 halogen situated at the site normally occupied by the hydroxyl group of T 4. The significantly wider entrance of the hormone-binding channel in sea bream TTR, in combination with its narrower cavity, provides a structural explanation for the different binding affinities of human and piscine TTR to T 3 and T 4 .

General and Comparative Endocrinology, 2000

Transthyretin (TTR) belongs to a group of proteins, which includes thyroxine-binding globulin and... more Transthyretin (TTR) belongs to a group of proteins, which includes thyroxine-binding globulin and albumin, that bind to and transport thyroid hormones in the blood. TTR is also indirectly implicated in the carriage of vitamin A through the mediation of retinol-binding protein (RBP). It was first identified in 1942 in human serum and cerebrospinal fluid and was formerly called prealbumin for its ability to migrate faster than serum albumin on electrophoresis of whole plasma. It is a single polypeptide chain of 127 amino acids (14,000 Da) and is present in the plasma as a tetramer of noncovalently bound monomers. The major sites of synthesis of TTR in eutherian mammals, marsupials, and birds are the liver and choroid plexus but in reptiles it is synthesised only in the choroid plexus. The observation that TTR is strongly expressed in the choroid plexus but not in the liver of the stumpy-tailed lizard and the strong conservation of expression in the choroid plexus from reptiles to mammals have been taken as evidence to suggest that extrahepatic synthesis of TTR evolved first. The identification and cloning of TTR from the liver of an amphibian, Rana catesbeiana, and a teleost fish, Sparus aurata, and its absence from the choroid plexus of both species suggest an alternative model for its evolution. Protein modelling studies are presented that demonstrate differences in the electrostatic characteristics of the molecule in human, rat, chicken, and fish, which may explain why, in contrast to TTR from human and rat, TTR from fish and birds preferentially binds triiodo-L-thyronine.

Biology of Reproduction, 2003

Prolactin (PRL) in fish is considered to be an osmoregulatory hormone, although some studies sugg... more Prolactin (PRL) in fish is considered to be an osmoregulatory hormone, although some studies suggest that it may influence the production of steroid hormones in the gonads. The objective of the present study was to establish if PRL is involved in reproduction of the gilthead seabream-a protandrous hermaphrodite. Adult and juvenile gilthead seabream received implants of estradiol-17␤ (E 2) for 1 wk during the breeding season, and the mRNA expressions of PRL and PRL receptor (sbPRLR) were determined. Northern blot analysis revealed a single pituitary PRL transcript, the expression of which was significantly reduced by E 2 treatment in adults but significantly increased in juvenile fish. In adult gonads, four sbPRLR transcripts of 1.1, 1.3, 1.9, and 2.8 kilobases were observed. A competitive reverse transcription-polymerase chain reaction was developed and used to determine how E 2 treatment alters expression of the gonadal sbPRLR gene. Seabream PRLR was detectable in all samples analyzed by this assay. Levels of sbPRLR mRNA increased significantly (50-fold) after E 2 treatment in adults, but a 24-fold decrease was measured in juveniles. Immunohistochemistry using specific polyclonal antibodies raised against an oligopeptide from the extracellular domain of sbPRLR detected the receptor in spermatogonia and oocytes. Taken together, the preceding results suggest that in the seabream, PRL may act on both testis and ovary via its receptor and that the stage of maturity influences this process. The full characterization and relative importance of the different transcripts of sbPRLR in eliciting the action of PRL in the gonads remain to be elucidated.

Annals of the New York Academy of Sciences, 1998

Journal of Molecular Neuroscience, 2008

To my family for the friendship and support, they are always present when I need. A great kiss to... more To my family for the friendship and support, they are always present when I need. A great kiss to my dear Sandra, she knows.... A big hug to the people "in the house" Nuno Macedo, Ricardo Eiras, Pedro Varão.