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- 4,9-Diaminoacridines and 4-Aminoacridines as Dual-Stage Antiplasmodial HitsPublication . Fonte, Mélanie; Tassi, Natália; Fontinha, Diana; Bóuzon-Arnáiz, Inês; Ferraz, Ricardo; Araújo, Maria J.; Fèrnandez-Busquets, Xavier; Prudêncio, Miguel; Gomes, Paula; Teixeira, CátiaMulti‐stage drugs have been prioritized in antimalarial drug discovery, as targeting more than one process in the Plasmodium life cycle is likely to increase efficiency, while decreasing the chances of emergence of resistance by the parasite. Herein, we disclose two novel acridine‐based families of compounds that combine the structural features of primaquine and chloroquine. Compounds prepared and studied thus far retained the in vitro activity displayed by the parent drugs against the erythrocytic stages of chloroquine‐sensitive and ‐resistant Plasmodium falciparum strains, and against the hepatic stages of Plasmodium berghei, hence acting as dual‐stage antiplasmodial hits.
- Absence of negative allelopathic effects of cylindrospermopsin and microcystin-LR on selected marine and freshwater phytoplankton speciesPublication . Pinheiro, Carlos; Azevedo, Joana; Campos, Alexandre; Loureiro, Susana; Vasconcelos, VítorCyanobacterial toxins have been regarded by some researchers as allelopathic substances that could modulate the growth of competitors. Nevertheless, often the concentrations of toxins used are too high to be considered ecologically relevant. In this work we tested the hypothesis that microcystin-LR (MC-LR) and cylindrospermopsin (CYN) at ecologically relevant concentrations have no allelopathic effects on some species of phytoplankton. Extracts containing the toxins as well as pure MC-LR and CYN toxins were used to assess their effects on the growth rates of Nannochloropsis sp., Chlamydomonas reinhardtii, and Chlorella vulgaris. Cyanobacterial crude extracts induced more pronounced effects on growth rates than pure toxins. Microcystis aeruginosa and Aphanizomenon ovalisporum crude extracts containing MC-LR and CYN at 0.025–2.5 mg l−1 stimulated growth rates of microalgae, whereas A. ovalisporum crude extracts containing 2.5 mg l−1 of CYN strongly inhibited growth rates of microalgae after 4 and 7 days of exposure. MC-LR and CYN at environmentally occurring concentrations were unable to affect negatively the growth of microalgae, and therefore these molecules may play roles other than allelopathy in natural ecosystems.
- Adipocyte proteome and secretome influence inflammatory and hormone pathways in gliomaPublication . Almeida, Joana; Costa, J.; Coelho, Pedro; Cea, V.; Galesio, M.; Noronha, J. P.; Diniz, M. S.; Prudêncio, Cristina; Soares, R.; Sala, C.; Fernandes, RúbenGliomas represent the most common primary malignant brain tumors in adults, with an extremely poor prognosis. Among several risk factors, lifestyle was also recently identified as a major risk factor for the development of primary glioma. In the present study, we explore the relationship between obesity and glioma in a cellular model. Thus, we have study the influence of adipocytes secretome on glioma cell line GL261. Using the 3T3-L1 adipocyte cell line, and its conditioned medium (adipokines-enriched medium), we showed that adipocyte-released factors relate with glioma angiogenic, growth, hormones and metabolic behavior by MALDI-TOF-MS and proteomic array analysis. In a first view, STI1, hnRNPs and PGK1 are under expressed on CGl. Similarly, both carbonic anhydrase and aldose reductase are even suppressed in glioma cells that grown under adipokines-enriched environment. Contrariwise, RFC1, KIF5C, ANXA2, N-RAP and RACK1 are overexpressed in GL261 cell the in the presence of the adipokines-enriched medium. We further identified the factors that are released by adipocyte cells, and revealed that several pro-inflammatory and angiogenic factors, such as IL-6, IL-11, LIF, PAI-1, TNF-α, endocan, HGF, VEGF IGF-I, were secreted to the medium into a high extent, whereas TIMP-1 and SerpinE1 were under expressed on CGl. This study discloses an interesting in vitro model for the study of glioma biology under a "obesity" environment, that can be explored for the understanding of cancer cells biology, for the search of biomarkers, prognostic markers and therapeutic approaches.
- Adipocyte Secreted Factors Enhance Aggressiveness of Prostate Carcinoma CellsPublication . Moreira, Ângela; Pereira, Sofia S.; Costa, Madalena; Morais, Tiago; Pinto, Ana; Fernandes, Rúben; Monteiro, Mariana P.Obesity has been associated with increased incidence and risk of mortality of prostate cancer. One of the proposed mechanisms underlying this risk association is the change in adipokines expression that could promote the development and progression of the prostate tumor cells. The main goal of this study was to evaluate the effect of preadipocyte and adipocyte secretome in the proliferation, migration and invasion of androgen independent prostate carcinoma cells (RM1) and to assess cell proliferation in the presence of the adiposity signals leptin and insulin. RM1 cells were co-cultured in with preadipocytes, adipocytes or cultured in their respective conditioned medium. Cell proliferation was assessed by flow cytometry and XTT viability test. Cell migration was evaluated using a wound healing injury assay of RM1 cells cultured with conditioned media. Cellular invasion of RM1 cells co-cultured with adipocytes and preadipocytes was assessed using matrigel membranes. Preadipocyte conditioned medium was associated with a small increase in RM1 proliferation, while adipocytes conditioned media significantly increased RM1 cell proliferation (p<0.01). Adipocytes also significantly increased the RM1 cells proliferation in co-culture (p <0.01). Cell migration was higher in RM1 cells cultured with preadipocyte and adipocyte conditioned medium. RM1 cell invasion was significantly increased after co-culture with preadipocytes and adipocytes (p <0.05). Insulin also increased significantly the cell proliferation in contrast to leptin, which showed no effect. In conclusion, prostate carcinoma cells seem to be influenced by factors secreted by adipocytes that are able to increase their ability to proliferate, migrate and invade.
- Adipocyte secretome increases radioresistance of malignant melanocytes by improving cell survival and decreasing oxidative statusPublication . Coelho, Pedro; Silva, Liliana; Faria, Isabel; Vieira, Mónica; Monteiro, Armanda; Pinto, Gabriela; Prudêncio, Cristina; Fernandes, Rúben; Soares, RaquelRadiotherapy is a treatment option for the majority of malignancies. However, because melanoma is known to be radioresistant, the use of ionizing radiation as an adjuvant therapy in cutaneous melanoma patients is ineffective. Obesity has now been recognized as a risk factor for melanoma. High adiposity is generally associated with a more pro-oxidative status. Oxidative stress is a major player in radiation therapy and also a common link between obesity and cancer. Several adipocyte-released proteins are known to have a role in controlling cellular growth and pro-survival signaling. For that reason, we investigated the influence of 3T3-L1 mature adipocyte secretome in B16-F10 malignant melanocyte radiosensitivity. We evaluated B16-F10 cell survival and redox homeostasis when exposed to four daily doses of ionizing radiation (2 Gy per day) up to a total of 8 Gy in a medical linear accelerator. B16-F10 melanocytes exhibited slight alterations in survival, catalase activity, nitrative stress and total oxidant concentration after the first 2 Gy irradiation. The motility of the melanocytes was also delayed by ionizing radiation. Subsequent irradiations of the malignant melanocytes led to more prominent reductions in overall survival. Remarkably, 3T3-L1 adipocyte-secreted molecules were able to increase the viability and migration of melanocytes, as well as lessen the pro-oxidant burden induced by both the single and cumulative X-ray doses. In vitro adipocyte-released factors protected B16-F10 malignant melanocytes from both oxidative stress and loss of viability triggered by radiation, enhancing the radioresistant phenoyype of these cells with a concomitant activation of the AKT signaling pathway These results both help to elucidate how obesity influences melanoma radioresistance and support the usage of conventional medical linear accelerators as a valid model for the in vitro radiobiological study of tumor cell lines.
- Affinity coefficient for clustering autoregressive moving average modelsPublication . Nascimento, Ana Paula; Oliveira, Alexandra; Faria, Brígida Mónica; Pimenta, Rui; Vieira, Mónica; Prudêncio, Cristina; Nicolau, Helena BacelarIn various fields, such as economics, finance, bioinformatics, geology, and medicine, namely, in the cases of electroencephalogram, electrocardiogram, and biotechnology, cluster analysis of time series is necessary. The first step in cluster applications is to establish a similarity/dissimilarity coefficient between time series. This article introduces an extension of the affinity coefficient for the autoregressive expansions of the invertible autoregressive moving average models to measure their similarity between them. An application of the affinity coefficient between time series was developed and implemented in R. Cluster analysis is performed with the corresponding distance for the estimated simulated autoregressive moving average of order one. The primary findings indicate that processes with similar forecast functions are grouped (in the same cluster) as expected concerning the affinity coefficient. It was also possible to conclude that this affinity coefficient is very sensitive to the behavior changes of the forecast functions: processes with small different forecast functions appear to be well separated in different clusters. Moreover, if the two processes have at least an infinite number of π- weights with a symmetric signal, the affinity value is also symmetric.
- Angiogenesis in Schistosoma haematobium-associated urinary bladder cancerPublication . Dematei, Anderson; Fernandes, Rúben; Soares, Raquel; Alves, Helena; Richter, Joachim; Botelho, Monica C.Schistosoma haematobium, a parasitic flatworm that infects more than 100 million people, mostly in the developing world, is the causative agent of urogenital schistosomiasis, and is associated with a high incidence of squamous cell carcinoma (SCC) of the bladder. During infection, eggs are deposited in the bladder causing an intense inflammatory reaction. Angiogenesis is defined as the formation of new blood vessels from preexisting ones and is recognized as a key event in cell proliferation and carcinogenesis and spread of malignant lesions. A growing amount of evidence points to angiogenesis playing a key role in schistosomiasis-associated bladder cancer. Thus, identifying biomarkers of this process plays an important role in the study of cancer. Here, we review recent findings on the role of angiogenesis in bladder cancer and the growth factors that induce and assist in their development, particularly SCC of the bladder associated to urogenital schistosomiasis.
- Anti-Angiogenic Properties of Cafestol and Kahweol Palmitate Diterpene EstersPublication . Moeenfard, Marzieh; Cortez, Alice; Machado, Vera; Costa, Raquel; Luís, Carla; Coelho, Pedro; Soares, Raquel; Alves, Arminda; Borges, Nuno; Santos, AlejandroEpidemiological studies support the association of coffee-specific diterpenes, with various beneficial health effects. Although anti-antiangiogenic properties of free cafestol and kahweol have been recently described, available data regarding their esterified form, in particular palmitate esters as the main diterpene esters present in coffee, are still rare. Given that angiogenesis plays an important role in many pathological conditions, including cancer growth and metastasis, this study aimed to assess and compare the potential anti-angiogenic effects of cafestol palmitate (CP) and kahweol palmitate (KP) in an in vitro angiogenesis model. According to our findings, both compounds inhibited angiogenesis steps on human microvascular endothelial cells (HMVECs), although a more significant effect was observed for KP. Compared to control, HMVECs viability decreased in a dose-dependent manner upon incubation either with CP or KP. Concentrations of 75 and 100 μM of each compound were cytotoxic. Cell proliferation was also dramatically reduced by both diterpene esters at 50 μM, although KP had a stronger inhibitory effect. However, CP and KP did not induce apoptosis on HMVECs. Both compounds reduced cell migration, but this effect was only statistically significant after KP incubation. Inhibition of VEGFR2 expression and its downstream effector Akt, but not Erk, was also observed in CP- and KP-treated HMVECs. These findings were confirmed using ELISA assay for phosphorylated (active) VEGFR-2. Taken together, these data indicate that both CP and KP can be considered potent compounds against angiogenesis-dependent disorders. Our findings further indicate that KP exerts more potent anti-angiogenic effects than CP, in most of assays.
- Anti-Pneumocystis carinii and antiplasmodial activities of primaquine-derived imidazolidin-4-onesPublication . Vale, Nuno; Collins, Margaret S.; Gut, Jiri; Ferraz, Ricardo; Rosenthal, Philip J.; Cushion, Melanie T.; Moreira, Rui; Gomes, PaulaA series of primaquine-derived imidazolidin-4-ones were screened for their in vitro activity against Pneumocystis carinii and Plasmodium falciparum W2 strain. Most compounds were active against P. carinii above 10 lg/mL and displayed slight to marked activity. The imidazolidin-4-ones most active against P. carinii were also those most active antiplasmodial agents, in the lM range. One of the tested imidazolidin-4-ones was slightly more active than the parent primaquine and may represent a lead com pound for the development of novel anti-P. carinii 8-aminoquinolines with increased stability and resistance to metabolic inactivation.
- Antibacterial activity of Ionic Liquids based on ampicillin against resistant bacteriaPublication . Ferraz, Ricardo; Teixeira, Vânia; Rodrigues, Débora; Prudêncio, Cristina; Fernandes, Rúben; Noronha, João Paulo; Petrovski, Zeljko; Branco, LuísAntibacterial activity of novel Active Pharmaceutical Ingredient Ionic Liquids (API-ILs) based on ampicillin anion [Amp] have been evaluated. They showed growth inhibition and bactericidal properties on some sensitive bacteria and especially some Gram-negative resistant bacteria when compared to the [Na][Amp] and the initial bromide and chloride salts. For these studies were analysed the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBIC) against sensitive Gram-negative bacteria Escherichia coli ATCC 25922 and Klebsiella pneumonia (clinically isolated), as well as sensitive Gram positive S. Aureus ATCC 25923, Staphylococcus epidermidis and Enterococcus faecalis and completed using clinically isolated resistent strains: E. coli TEM CTX M9, E. coli CTX M2 and E. coli AmpC Mox. From the obtained MIC values of studied APIs-ILs and standard [Na][Amp] were derived RDIC values (relative decrease of inhibitory concentration). High RDIC values of [C16Pyr][Amp] especially against two resistant Gram-negative strains E. coli TEM CTX M9 (RDIC>1000) and E. coli CTX M2 (RDIC>100) point clearly to a potential promising role of APIs-ILs as antimicrobial drugs especially against resistant bacterial strains.