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- Potentional radiosensitizer effect of TUDCA in a obesity model of brain tumor cellsPublication . Silva, Liliana; Almeida, Joana; Coelho, Pedro; Faria, Isabel; Monteiro, Armanda; Soares, Raquel; Vieira, Mónica; Prudêncio, Cristina; Fernandes, RúbenObesity may play an important role in the biology of seve ral types of cancer, but the correlation with glioma Is still not very well defined. Former studies indicated that obesity may be related with an decreased resistance to radiation and increased redox status in brain tumors. Since radiothetapy is the most commonly treatment modality used in this type of tumor, we creale a new model of experiments to determinate the influence of obesity in glioma cells [n the presence of radiation with an imbalance of redox status, BC3H1 glioma cells were treated with t-BOOH (150~M), TUDCA (25~M) and a mix of t-BOOH and TUOCA{150~M and 25~M respectively) in serum-free OMEM or conditioned media (CM) from differentiated 3T3-L 1 adj pocytes. Afterwards the cells were irradiated with a total dose of 2 Gy. Subsequently BC3H1 viability was evaluated, by MTT assay, after 4 and 12 hours. We observed an increase in viability In all cells treated solely with 3T3-L 1 eM. Interestingly, in the presence of CM plus TUDCA or t-BOOH, the viability of 6C3H1 was inferior of TUOCA or t~BOOH treatments alone, this effect was independent of irradia tion. After 12 hours the I/iability of the glioma cells was significantly higher on irradiated ceUs treated only with eM, this effect was not yet observed at the 4 hours time point But, in the presence of mix of t~BOOH and TUDCA, with eM and irradiation the cells viability decrea se significanUy. The 3T3-L 1 Me increase (he cell viabrlity in the presence of radiation or not, after 12 hours expose" But in the presence of oxidatIve inducer and, In specially, with the antioxidant TUDCA, the BC3Hi viability significantly decrease. So, we observed a potential radiosensitfzer effect of TUDCA in BC3H1 in the presence of 3T3-L1 adipocytes.
- 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.
- Adipocyte-released factors enhance melanocyte’s proliferation and motilityPublication . Fernandes, Rúben; Coelho, Pedro; Almeida, Joana; Prudêncio, Cristina; Soares, RaquelObesity, favored by the modern lifestyle, acquired epidemic proportions nowadays. Obesity has been associated with various major causes of death and morbidity including malignant neoplasms. Cutaneous melanoma incidence rates have also been increasing uring the last four decades in several countries. Obesity involvement in melanoma etiology has been recognized, but the implicated mechanisms remain unclear. We propose to address the above relationship and investigate the mechanism interplaying between obesity and an increased risk of melanoma onset.
- Quinoxaline-1, 4-dioxide derivatives inhibitory action in melanoma and brain tumor cellsPublication . Silva, Liliana; Coelho, Pedro; Soares, Raquel; Prudêncio, Cristina; Vieira, MónicaQuinoxaline-1,4-dioxide derivatives are synthetic heterocyclic compounds with multiple biological and pharmacological effects. In this study, we investigated the bioactivity of five quinoxaline-1,4-di-N-oxides derivatives in different animal cell lines.
- 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.
- Xanthohumol-supplemented beer modulates angiogenesis and inflammation in a skin wound healing model. Involvement of local adipocytesPublication . Negrão, Rita; Costa, Raquel; Duarte, Delfim; Gomes, Tiago Taveira; Coelho, Pedro; Guimarães, João T.; Guardão, Luísa; Azevedo, Isabel; Soares, RaquelAngiogenesis and inflammation are two intermingled processes that play a role in wound healing. Nevertheless, whenever exacerbated, these processes result in nonhealing wounds. Xanthohumol (XN), a beer-derived polyphenol, inhibits these processes in many physiopathological situations. This study aimed at examining whether XN ingestion affects wound healing. Wistar rats drinking water, 5% ethanol, stout beer (SB) or stout beer supplemented with 10 mg/L XN (Suppl SB) for 4 weeks, were subjected to a 1.5 cm full skin-thickness longitudinal incision, and further maintained under the same beverage conditions for another week. No differences in beverage consumption or body weight were found throughout the study but food intake decreased in every group relative to controls. Consumption of Suppl SB resulted in decreased serum VEGF levels (18.42%), N-acetylglucosaminidase activity (27.77%), IL1β concentration (9.07%), and NO released (77.06%), accompanied by a reduced redox state as observed by increased GSH/GSSG ratio (to 198.80%). Also, the number of blood vessels within the wound granulation tissue seems to reduce in animals drinking Suppl SB (23.08%). Interestingly, SB and primarily Suppl SB showed a tendency to increase adipocyte number (to 194.26% and 156.68%, respectively) and reduce adipocyte size (4.60% and 24.64%, respectively) within the granuloma. Liver function and metabolism did not change among the animal groups as analyzed by plasma biochemical parameters, indicating no beverage toxicity. This study shows that XN intake in its natural beer context reduced inflammation, oxidative stress, and angiogenesis, ameliorating the wound healing process, suggesting that this polyphenol may exert beneficial effect as a nutritional supplement.
- Melanoma and obesity: Should antioxidant vitamins be addressed?Publication . Oliveira, Sofia; Coelho, Pedro; Prudêncio, Cristina; Vieira, Mónica; Soares, Raquel; Guerreiro, Susana G.; Fernandes, RúbenMelanoma is an aggressive form of skin cancer refractory to conventional therapies. Obesity has reached epidemic dimensions acting as a risk factor for several cancer types, such as melanoma. Several reactive species of oxygen are also involved in melanoma initiation and progression. Low levels of antioxidant content and/or activity in lightly pigmented cells could expose them to an extremely oxidative environment and rise the susceptibility to oxidative damage and consequently loss of cell homeostasis. Despite the knowledge about melanoma biology, pathogenesis and developed therapies, is extremely important to understand the antioxidant modulation of melanoma under an environment of obesity, especially the effect of some natural compounds of the diet, such as antioxidant vitamins A, C and E and selenium in order to establish alternatives to conventional therapies, which are known to be ineffective against melanoma.
- Evaluation of quinoxaline-1,4-dioxide and derivatives biological activity in normal and tumour cellPublication . Silva, Liliana; Coelho, Pedro; Soares, Raquel; Prudêncio, Cristina; Vieira, MónicaQuinoxaline derivatives are synthetic heterocyclic compounds with multiples pharmacological applications and biological effects. Previous studies of our group about the biological activity in eukaryotic and prokaryotic microbial models with quinoxaline-1,4-dioxide (QNX) derivatives concluded a selective antimicrobial activity in gram negative strains. To further evaluate these compounds’ potential, we investigated the biologic activity in vitro of this chemical structures in normal and tumour cells lines.
- Xanthohumol and 8-prenylnaringenin reduce type 2 diabetes–associated oxidative stress by downregulating galectin-3Publication . Luís, Carla; Costa, Raquel; Rodrigues, Ilda; Castela, Ângela; Coelho, Pedro; Guerreiro, Susana; Gomes, Joana; Reis, Celso; Soares, RaquelGalectin-3 (Gal3) expression is associated with accumulation of Advanced Glycation End products (AGE), a common feature in diabetes mellitus (DM). The role of Gal3 in oxidative stress is, however, controversial, being considered in the literature to play either a protective role or exacerbating disease. :Herein, we examined the interplay between Gal3 and oxidative stress in a high-fat diet -induced type 2 DMC57Bl/6 mice model. Because natural polyphenols are known to play antioxidant and anti-inflammatory roles and to modulate metabolic activity, we further evaluated the effect of xanthohumol and 8-prenylnaringenin polyphenols in this crosstalk. Gal3 expression was accompanied by 3-nitrotyrosine and AGE production in liver and kidney of diabetic mice compared to healthy animals (fed with standard diet). Oral supplementation with polyphenols decreased the levels of these oxidative biomarkers as evaluated by immunohistochemistry and western blotting. Interestingly, blocking Gal3 by incubating human microvascular endothelial cells with modified citrus pectin increased 3-nitrotyrosine protein expression. These findings imply that Gal3 overexpression is probably controlling oxidative stress in endothelial cells. In conclusion, our results indicate that supplementation with 8-prenylnaringenin or xanthohumol reverses diabetes-associated oxidation in liver and kidney, and consequently decreases this diabetic biomarker that predispose to cardiovascular complications.
- Effect of Adipocyte Secretome in Melanoma Progression and Vasculogenic MimicryPublication . Coelho, Pedro; Almeida, Joana; Prudêncio, Cristina; Fernandes, Rúben; Soares, RaquelObesity, favored by the modern lifestyle, acquired epidemic proportions nowadays. Obesity has been associated with various major causes of death and morbidity including malignant neoplasms. This increased prevalence has been accompanied by a worldwide increase in cutaneous melanoma incidence rates during the last decades. Obesity involvement in melanoma aetiology has been recognized, but the implicated mechanisms remain unclear. In the present study, we address this relationship and investigate the influence of adipocytes secretome on B16-F10 and MeWo melanoma cell lines. Using the 3T3-L1 adipocyte cell line, as well as ex vivo subcutaneous (SAT) and visceral (VAT) adipose tissue conditioned medium, we were able to show that adipocyte-released factors play a dual role in increasing melanoma cell overall survival, both by enhancing proliferation and decreasing apoptosis. B16-F10 cell migration and cell-cell and cell-matrix adhesion capacity were predominantly enhanced in the presence of SAT and VAT released factors. Melanocytes morphology and melanin content were also altered by exposure to adipocyte conditioned medium disclosing a more dedifferentiated phenotype of melanocytes. In addition, exposure to adipocyte-secreted molecules induced melanocytes to rearrange, on 3D cultures, into vessel-like structures, and generate characteristic vasculogenic mimicry patterns. These findings are corroborated by the released factors profile of 3T3-L1, SAT, and VAT assessed by microarrays, and led us to highlight the mechanisms by which adipose secretome from sub-cutaneous or visceral depots promote melanoma progression.