Helena Marcelino
Verified @gmail.com
Health Sciences Research Center (CICS-UBI); University of Beira Interior
University of Beira Interior
Scopus Publications
Scopus Publications
Ângelo Luís, Helena Marcelino, Fernanda Domingues, Luísa Pereira, and José Francisco Cascalheira
MDPI AG
Gliomas are aggressive malignant brain tumors, with poor prognosis despite available therapies, raising the necessity for finding new compounds with therapeutic action. Numerous preclinical investigations evaluating resveratrol’s anti-tumor impact in animal models of glioma have been reported; however, the variety of experimental circumstances and results have prevented conclusive findings about resveratrol’s effectiveness. Several databases were searched during May 2023, ten publications were identified, satisfying the inclusion criteria, that assess the effects of resveratrol in murine glioma-bearing xenografts. To determine the efficacy of resveratrol, tumor volume and animal counts were retrieved, and the data were then subjected to a random effects meta-analysis. The influence of different experimental conditions and publication bias on resveratrol efficacy were evaluated. Comparing treated to untreated groups, resveratrol administration decreased the tumor volume. Overall, the effect’s weighted standardized difference in means was −2.046 (95%CI: −3.156 to −0.936; p-value < 0.001). The efficacy of the treatment was observed for animals inoculated with both human glioblastoma or rat glioma cells and for different modes of resveratrol administration. The combined administration of resveratrol and temozolomide was more effective than temozolomide alone. Reducing publication bias did not change the effectiveness of resveratrol treatment. The findings suggest that resveratrol slows the development of tumors in animal glioma models.
Nádia Oliveira, Helena Marcelino, Regina Azevedo, and Ignacio Verde
Springer Science and Business Media LLC
Nádia Oliveira, Helena Marcelino, Regina Azevedo, and Ignacio Verde
Springer Science and Business Media LLC
Helena Marcelino, Tiago M.A. Carvalho, Joana Tomás, Francisca I. Teles, Ana C. Honório, Carolina B. Rosa, Ana R. Costa, Bruno M. Costa, Cecília R.A. Santos, Ana M. Sebastião,et al.
Elsevier BV
Glioblastoma (GBM) is the most common brain primary tumour. Hypoxic regions in GBM are associated to tumour growth. Adenosine accumulates in hypoxic regions and can affect cell proliferation and survival. However, how proliferating GBM cells respond/adapt to increased adenosine levels compared to human astrocytes (HA) is not clarified and was addressed in the present work. GBM cell lines and HA were treated for 3 days with test drugs. 30µM-Adenosine caused a 46%±3% (P<0.05) reduction of cell proliferation/viability in HA, through an adenosine receptor-independent mechanism, but had no effect in glioblastoma cell lines U87MG, U373MG and SNB19. Contrastingly, inhibition of adenosine phosphorylation (using the adenosine kinase (ADK) inhibitor 5-iodotubercidin (25µM)), produced a strong and similar decrease on cell proliferation in both HA and glioblastoma cells. The effect of adenosine on HA proliferation/viability was potentiated by 100µM-homocysteine. Combined application of 30µM-adenosine and 100µM-homocysteine reduced cell proliferation/viability in all three GBM cell lines, but this reduction was much lower than that observed in HA. Adenosine alone did not induce cell death, assessed by LDH release, both in HA and GBM cells, but potentiated cytotoxic effect of homocysteine in HA and in U87MG and U373MG cells. Results show a strong attenuation of adenosine anti-proliferative effect in GBM cells compared to HA, probably resulting from increased adenosine elimination by ADK, suggesting a proliferative-prone adaptation of tumour cells to increased adenosine levels.
Julie Calonne, Helena Marcelino, Christelle Veyrat-Durebex, Isabelle Scerri, and Abdul G. Dulloo
Springer Science and Business Media LLC
Abstract Background/Objectives Catch-up growth, an important risk factor for later obesity and type 2 diabetes, is often characterized by a high rate of fat deposition associated with hyperinsulinemia and glucose intolerance. We tested here the hypothesis that refeeding on a high-fat diet rich in essential polyunsaturated fatty acids (ePUFA) improves glucose homeostasis primarily by enhancing insulin sensitivity in skeletal muscles and adipose tissues. Methods Rats were caloric restricted for 2 weeks followed by 1–2 weeks of isocaloric refeeding on either a low-fat (LF) diet, a high-fat (HF) diet based on animal fat and high in saturated and monounsaturated fatty acids (HF SMFA diet), or a HF diet based on vegetable oils (1:1 mixture of safflower and linseed oils) and rich in the essential fatty acids linoleic and α-linolenic acids (HF ePUFA diet). In addition to measuring body composition and a test of glucose tolerance, insulin sensitivity was assessed during hyperinsulinemic-euglycemic clamps at the whole-body level and in individual skeletal muscles and adipose tissue depots. Results Compared to animals refed the LF diet, those refed the HF-SMFA diet showed a higher rate of fat deposition, higher plasma insulin and glucose responses during the test of glucose tolerance, and markedly lower insulin-stimulated glucose utilization at the whole body level (by a-third to a-half) and in adipose tissue depots (by 2–5 folds) during insulin clamps. While refeeding on the ePUFA diet prevented the increases in fat mass and in plasma insulin and glucose, the results of insulin clamps revealed that insulin-stimulated glucose utilization was not increased in skeletal muscles and only marginally higher in adipose tissues and at the whole-body level. Conclusions These results suggest only a minor role for enhanced insulin sensitivity in the mechanisms by which diets high in ePUFA improves glucose homeostasis during catch-up growth.
Ângelo Luís, Helena Marcelino, Carolina Rosa, Fernanda Domingues, Luísa Pereira, and José Francisco Cascalheira
Elsevier BV
Glioblastoma multiforme (GBM) is the most frequent and aggressive malignant brain tumour, with a poor prognosis despite available surgical and radio-chemotherapy, rising the necessity for searching alternative therapies. Several preclinical studies evaluating the efficacy of cannabinoids in animal models of GBM have been described, but the diversity of experimental conditions and of outcomes hindered definitive conclusions about cannabinoids efficacy. A search in different databases (Pubmed, Web of Science, Scopus and SciELO) was conducted during June 2019 to systematically identify publications evaluating the effects of cannabinoids in murine xenografts models of GBM. The tumour volume and number of animals were extracted, being a random effects meta-analysis of these results performed to estimate the efficacy of cannabinoids. The impact of different experimental factors and publication bias on the efficacy of cannabinoids was also assessed. Nine publications, which satisfied the inclusion criteria, were identified and subdivided in 22 studies involving 301 animals. Overall, cannabinoid therapy reduced the fold of increase in tumour volume in animal models of GBM, when compared with untreated controls. The overall weighted standardized difference in means (WSDM) for the effect of cannabinoids was -1.399 (95% CI: -1.900 to -0.898; P-value<0.0001). Furthermore, treatment efficacy was observed for different types of cannabinoids, alone or in combination, and for different treatment durations. Cannabinoid therapy was still effective after correcting for publication bias. The results indicate that cannabinoids reduce the tumour growth in animal models of GBM, even after accounting for publication bias.
Helena Marcelino, Vanda C. Nogueira, Cecília R.A. Santos, Patrícia Quelhas, Tiago M.A. Carvalho, João Fonseca‐Gomes, Joana Tomás, Maria J. Diógenes, Ana M. Sebastião, and José F. Cascalheira
Wiley
Brain adenosine concentrations can reach micromolar concentrations in stressful situations such as stroke, neurodegenerative diseases or hypoxic regions of brain tumours. Adenosine can act by receptor‐independent mechanism 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.
Solange Glória, João Marques, Joana Feiteiro, Helena Marcelino, Ignacio Verde, and Elisa Cairrão
Elsevier BV
Some studies in animals suggest that TBT may constitute a risk factor for cardiovascular diseases. Hence, the main purpose of this study was to investigate in human umbilical artery (HUA) the effect of TBT on vascular reactivity, manly in serotonin (5-HT) and histamine receptors. Using standard organ bath techniques, rings of HUA without endothelium were contracted by 5-HT and histamine. We also investigated the effect of TBT on the expression of the receptors using Real-time PCR. The results show that TBT short term effects include concentration-dependent relaxation. Moreover, at long term exposures, the arteries treated with 100 μM of TBT do not have contraction capacity when 5-HT is added, and the gene expression of 5-HT2A receptor decrease. Regarding histamine, it was demonstrated that TBT induces a concentration-dependent relaxation and the H1 gene expression levels decrease. In conclusion TBT modifies the activity and expression of 5-HT and histamine receptors.
A. R. Costa, H. Marcelino, I. Gonçalves, T. Quintela, J. Tomás, A. C. Duarte, A. M. Fonseca, and C. R. A. Santos
Wiley
The choroid plexus (CP) epithelium is a unique structure in the brain that forms an interface between the peripheral blood on the basal side and the cerebrospinal fluid (CSF) on the apical side. It is a relevant source of many polypeptides secreted to the CSF with neuroprotective functions and also participates in the elimination and detoxification of brain metabolites, such as β‐amyloid (Aβ) removal from the CSF through transporter‐mediated influx. The CP is also a target tissue for sex hormones (SHs) that have recognised neuroprotective effects against a variety of insults, including Aβ toxicity and oxidative stress in the central nervous system. The present study aimed to understand how SHs modulate Aβ‐induced oxidative stress in a CP cell line (Z310 cell line) by analysing the effects of Aβ1–42 on oxidative stress, mitochondrial function and apoptosis, as well as by assessing how 17β‐oestradiol (E2) and 5α‐dihydrotestosterone (DHT) modulated these effects and the cellular uptake of Aβ1–42 by CP cells. Our findings show that E2 and DHT treatment reduce Aβ1–42‐induced oxidative stress and the internalisation of Aβ1–42 by CP epithelial cells, highlighting the importance of considering the background of SHs and therefore sex‐related differences in Aβ metabolism and clearance by CP cells.
T. Quintela, H. Marcelino, M. J. Deery, R. Feret, J. Howard, K. S. Lilley, T. Albuquerque, I. Gonçalves, A. C. Duarte, and C. R. A. Santos
Wiley
The choroid plexus (CP) epithelium is a unique structure in the brain that forms an interface between the peripheral blood and the cerebrospinal fluid (CSF), which is mostly produced by the CP itself. Because the CP transcriptome is regulated by the sex hormone background, the present study compared gene/protein expression profiles in the CP and CSF from male and female rats aiming to better understand sex‐related differences in CP functions and brain physiology. We used data previously obtained by cDNA microarrays to compare the CP transcriptome between male and female rats, and complemented these data with the proteomic analysis of the CSF of castrated and sham‐operated males and females. Microarray analysis showed that 17 128 and 17 002 genes are expressed in the male and female CP, which allowed the functional annotation of 141 and 134 pathways, respectively. Among the most expressed genes, canonical pathways associated with mitochondrial dysfunctions and oxidative phosphorylation were the most prominent, whereas the most relevant molecular and cellular functions annotated were protein synthesis, cellular growth and proliferation, cell death and survival, molecular transport, and protein trafficking. No significant differences were found between males and females regarding these pathways. Seminal functions of the CP differentially regulated between sexes were circadian rhythm signalling, as well as several canonical pathways related to stem cell differentiation, metabolism and the barrier function of the CP. The proteomic analysis identified five down‐regulated proteins in the CSF samples from male rats compared to females and seven proteins exhibiting marked variation in the CSF of gonadectomised males compared to sham animals, whereas no differences were found between sham and ovariectomised females. These data clearly show sex‐related differences in CP gene expression and CSF protein composition that may impact upon neurological diseases.
Telma Quintela, Helena Marcelino, Isabel Gonçalves, Filipa M. Patriarca, and Cecília R. A. Santos
Springer Science and Business Media LLC
Evidence from the literature suggests that testosterone (T) plays an important role in the neural structure, physiology, and function of the hippocampus (HP). However, many of the genes involved and underlying mechanisms remain to be elucidated. To shed light on this issue, we explored the transcriptome of HP in orchidectomized (OOX) rats to identify T-dependent gene expression in rat HP. RNA from OOX and sham HP animals were processed and measured by the Applied Biosystems microarray platform. The results showed a total of 271 genes differentially expressed between OOX vs. sham animals. Overall, T depletion resulted in the upregulation of 98 genes, including genes associated with neurogenesis and behavior. Of particular interest was the downregulation of 173 genes, with known functions, including signal transduction or neurological system processes. Our data shows that T depletion results in significantly altered hippocampal gene expression profiles and constitutes a starting tool to elucidating the molecular mechanisms involved in the action of androgens in the physiology of the HP.
Telma Quintela, Isabel Gonçalves, Laura C. Carreto, Manuel A. S. Santos, Helena Marcelino, Filipa M. Patriarca, and Cecília R. A. Santos
Public Library of Science (PLoS)
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.
Helena Marcelino, Christelle Veyrat-Durebex, Serge Summermatter, Delphine Sarafian, Jennifer Miles-Chan, Denis Arsenijevic, Fabio Zani, Jean-Pierre Montani, Josiane Seydoux, Giovanni Solinas,et al.
American Diabetes Association
Catch-up growth, a risk factor for type 2 diabetes, is characterized by hyperinsulinemia and accelerated body fat recovery. Using a rat model of semistarvation-refeeding that exhibits catch-up fat, we previously reported that during refeeding on a low-fat diet, glucose tolerance is normal but insulin-dependent glucose utilization is decreased in skeletal muscle and increased in adipose tissue, where de novo lipogenic capacity is concomitantly enhanced. Here we report that isocaloric refeeding on a high-fat (HF) diet blunts the enhanced in vivo insulin-dependent glucose utilization for de novo lipogenesis (DNL) in adipose tissue. These are shown to be early events of catch-up growth that are independent of hyperphagia and precede the development of overt adipocyte hypertrophy, adipose tissue inflammation, or defective insulin signaling. These results suggest a role for enhanced DNL as a glucose sink in regulating glycemia during catch-up growth, which is blunted by exposure to an HF diet, thereby contributing, together with skeletal muscle insulin resistance, to the development of glucose intolerance. Our findings are presented as an extension of the Randle cycle hypothesis, whereby the suppression of DNL constitutes a mechanism by which dietary lipids antagonize glucose utilization for storage as triglycerides in adipose tissue, thereby impairing glucose homeostasis during catch-up growth.
Gayathri Yepuri, Helena Marcelino, Yasaman Shahkhalili, Olivier Aprikian, Katherine Macé, Josiane Seydoux, Jennifer L. Miles, Jean-Pierre Montani, and Abdul G. Dulloo
Cambridge University Press (CUP)
The present study investigates whether excessive fat accumulation and hyperinsulinaemia during catch-up growth on high-fat diets are altered byn-6 andn-3 PUFA derived from oils rich in either linoleic acid (LA), α-linolenic acid (ALA), arachidonic acid (AA) or DHA. It has been shown that, compared with food-restricted rats refed a high-fat (lard) diet low in PUFA, those refed isoenergetically on diets enriched in LA or ALA, independently of then-6:n-3 ratio, show improved insulin sensitivity, lower fat mass and higher lean mass, the magnitude of which is related to the proportion of total PUFA precursors (LA+ALA) consumed. These relationships are best fitted by quadratic regression models (r2>0·8,P < 0·001), with threshold values for an impact on body composition corresponding to PUFA precursors contributing 25–30 % of energy intake. Isoenergetic refeeding on high-fat diets enriched in AA or DHA also led to improved body composition, with increases in lean mass as predicted by the quadratic model for PUFA precursors, but decreases in fat mass, which are disproportionately greater than predicted values; insulin sensitivity, however, was not improved. These findings pertaining to the impact of dietary intake of PUFA precursors (LA and ALA) and their elongated–desaturated products (AA and DHA), on body composition and insulin sensitivity, provide important insights into the search for diets aimed at counteracting the pathophysiological consequences of catch-up growth. In particular, diets enriched in essential fatty acids (LA and/or ALA) markedly improve insulin sensitivity and composition of weight regained, independently of then-6:n-3 fatty acid ratio.
Serge Summermatter, Helena Marcelino, Denis Arsenijevic, Antony Buchala, Olivier Aprikian, Françoise Assimacopoulos-Jeannet, Josiane Seydoux, Jean-Pierre Montani, Giovanni Solinas, and Abdul G. Dulloo
American Diabetes Association
OBJECTIVE Catch-up growth, a risk factor for later type 2 diabetes, is characterized by hyperinsulinemia, accelerated body-fat recovery (catch-up fat), and enhanced glucose utilization in adipose tissue. Our objective was to characterize the determinants of enhanced glucose utilization in adipose tissue during catch-up fat. RESEARCH DESIGN AND METHODS White adipose tissue morphometry, lipogenic capacity, fatty acid composition, insulin signaling, in vivo glucose homeostasis, and insulinemic response to glucose were assessed in a rat model of semistarvation-refeeding. This model is characterized by glucose redistribution from skeletal muscle to adipose tissue during catch-up fat that results solely from suppressed thermogenesis (i.e., without hyperphagia). RESULTS Adipose tissue recovery during the dynamic phase of catch-up fat is accompanied by increased adipocyte number with smaller diameter, increased expression of genes for adipogenesis and de novo lipogenesis, increased fatty acid synthase activity, increased proportion of saturated fatty acids in triglyceride (storage) fraction but not in phospholipid (membrane) fraction, and no impairment in insulin signaling. Furthermore, it is shown that hyperinsulinemia and enhanced adipose tissue de novo lipogenesis occur concomitantly and are very early events in catch-up fat. CONCLUSIONS These findings suggest that increased adipose tissue insulin stimulation and consequential increase in intracellular glucose flux play an important role in initiating catch-up fat. Once activated, the machinery for lipogenesis and adipogenesis contribute to sustain an increased insulin-stimulated glucose flux toward fat storage. Such adipose tissue plasticity could play an active role in the thrifty metabolism that underlies glucose redistribution from skeletal muscle to adipose tissue.
Reda M. El-Shishtawy, Cecília R. Santos, Isabel Gonçalves, Helena Marcelino, and Paulo Almeida
Elsevier BV
Some new monomethine cyanine dyes derived from quinoline and benzothiazole have been prepared and characterized by (1)H and (13)C NMR, FTIR, FABHRMS, and visible spectroscopy. The dyes containing amino and acetamido groups were conveniently synthesized by the condensation of two p-toluenesulfonate heterocyclic quaternary salts and were obtained in the forms of iodide, bromide, and tosylate counteranions. These dyes were compared to ethidium bromide as stains for DNA in electrophoretic gels. The overall results obtained for the sensitivity of these dyes suggest the suitability of acetamido moiety over the amine one and bromide as the counteranion when compared with iodide and tosylate, with a similar capacity of DNA detection in relation to the ethidium bromide stain over the concentration range of 1-3ng.