FCS - Artigos em Revistas Científicas Internacionais com Arbitragem Científica
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- 1,2-dihydroxyxanthone: effect on A375-C5 melanoma cell growth associated with interference with THP-1 human macrophage activityPublication . Silva, Viviana; Cerqueira, Fátima; Nazareth, Nair; Medeiros, R.; Sarmento, Amélia; Sousa, Emília; Pinto, MadalenaXanthones have been suggested as prospective candidates for cancer treatment. 1,2- dihydroxyxanthone (1,2-DHX) is known to interfere with the growth of several cancer cell lines. We investigated the effects of 1,2-DHX on the growth of the A375-C5 melanoma cell line and THP-1 human macrophage activity. 1,2-DHX showed a moderate growth inhibition of A375-C5 melanoma cells (concentration that causes a 50% inhibition of cell growth (GI50) = 55.0 ±2.3 µM), but strongly interfered with THP-1 human macrophage activity. Supernatants from lipopolysaccharide (LPS)-stimulated THP-1 macrophage cultures exposed to 1,2-DHX significantly increased growth inhibition of A375-C5 cells, when compared to supernatants from untreated LPS-stimulated macrophages or to direct treatment with 1,2-DHX only. 1,2-DHX decreased THP-1 secretion of interleukin-1β (IL-1β) and interleukin-10 (IL-10), but stimulated tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) production. This xanthone also inhibited nitric oxide (NO) production by RAW 264.7 murine macrophages, possibly through inhibition of inducible NO synthase production. In conclusion, these findings suggest a potential impact of 1,2-DHX in melanoma treatment, not only due to a direct effect on cancer cells but also by modulation of macrophage activity.
- 160 Fatty Acid Composition of Human Milk in a Portuguese Urban Population:Prospective Study from 7 Days to 16 Weeks of LactationPublication . Ribeiro, M; Balcão, Victor; Guimaraes, H; Rocha, G; Moutinho, Carla; Casal, S; Oliveira, B; Guerra, A
- 3,4-Methylenedioxymethamphetamine hepatotoxicity under the heat stress condition: novel insights from in vitro metabolomic studiesPublication . Araújo, Ana Margarida; Enea, Maria; Fernandes, Eduarda; Carvalho, Félix; de Lourdes Bastos, Maria; Carvalho, Márcia; Guedes de Pinho, PaulaHyperthermia has been extensively reported as a life-threatening consequence of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) abuse. In this work, we used a sensitive untargeted metabolomic approach based on gas chromatography-mass spectrometry to evaluate the impact of hyperthermia on the hepatic metabolic changes caused by MDMA. For this purpose, primary mouse hepatocytes were exposed to subtoxic (LC01 and LC10) and toxic (LC30) concentrations of MDMA for 24 h, at 37 or 40.5 °C (simulating body temperature increase after MDMA consumption), and alterations on both intracellular metabolome and extracellular volatilome were evaluated. Multivariate analysis showed that metabolic patterns clearly discriminate MDMA treated cells from control cells, both in normothermic and hyperthermic conditions. The metabolic signature was found to be largely common to MDMA subtoxic and toxic concentrations, although with evident differences in the magnitude of response, with metabolic changes significantly more pronounced at 40.5 °C. Discriminant metabolites associated with MDMA-induced hepatotoxicity are mostly involved in the amino acid metabolism, aminoacyl tRNA biosynthesis, glutathione metabolism, tricarboxylic acid cycle, and pyruvate metabolism. Moreover, our metabolomic findings were corroborated by classical toxicity parameters, demonstrating the high sensitivity of this omic approach to assess molecular-level effects. Overall, this study indicates that MDMA triggers significant metabolic alterations on hepatic cells, even at low concentrations, that are clearly exacerbated at high temperatures. These findings provide new metabolic pieces to solve the puzzle of MDMA's hepatotoxicity mechanism and emphasize the increased risks of MDMA abuse due to the thermogenic action of the drug.
- 3,4-Methylenedioxypyrovalerone (MDPV): in vitro mechanisms of hepatotoxicity under normothermic and hyperthermic conditionsPublication . Valente, Maria João; Araújo, Ana Margarida; Silva, Renata; Bastos, Maria de Lourdes; Carvalho, Félix; Guedes de Pinho, Paula; Carvalho, MárciaSynthetic cathinones have emerged in recreational drug markets as legal alternatives for classical amphetamines. Though currently banned in several countries, 3,4-methylenedioxypyrovalerone (MDPV) is one of the most commonly abused cathinone derivatives worldwide. We have recently reported the potential of MDPV to induce hepatocellular damage, but the underlying mechanisms responsible for such toxicity remain to be elucidated. Similar to amphetamines, a prominent toxic effect of acute intoxications by MDPV is hyperthermia. Therefore, the present in vitro study aimed to provide insights into cellular mechanisms involved in MDPV-induced hepatotoxicity and also evaluate the contribution of hyperthermia to the observed toxic effects. Primary cultures of rat hepatocytes were exposed to 0.2-1.6 mM MDPV for 48 h, at 37 or 40.5 °C, simulating the rise in body temperature that follows MDPV intake. Cell viability was measured through the MTT reduction and LDH leakage assays. Oxidative stress endpoints and cell death pathways were evaluated, namely the production of reactive oxygen and nitrogen species (ROS and RNS), intracellular levels of reduced (GSH) and oxidized (GSSG) glutathione, adenosine triphosphate (ATP) and free calcium (Ca(2+)), as well as the activities of caspases 3, 8 and 9, and nuclear morphological changes with Hoechst 33342/PI double staining. At 37 °C, MDPV induced a concentration-dependent loss of cell viability that was accompanied by GSH depletion, as one of the first signs of toxicity, observed already at low concentrations of MDPV, with negligible changes on GSSG levels, followed by accumulation of ROS and RNS, depletion of ATP contents and increases in intracellular Ca(2+) concentrations. Additionally, activation of caspases 3, 8, and 9 and apoptotic nuclear morphological changes were found in primary rat hepatocytes exposed to MDPV, indicating that this cathinone derivative activates both intrinsic and extrinsic apoptotic death pathways. The cytotoxic potential of MDPV and all the studied endpoints were markedly aggravated under hyperthermic conditions (40.5 °C). In conclusion, these data suggest that MDPV toxicity in primary rat hepatocytes is mediated by oxidative stress, subsequent to GSH depletion and increased ROS and RNS accumulation, mitochondrial dysfunction, and impairment of Ca(2+) homeostasis. Furthermore, the rise in body temperature subsequent to MDPV abuse greatly exacerbates its hepatotoxic potential.
- 4,4′-(1,8-Naphthalene-1,8-diyl)dibenzonitrilePublication . Lima, Carlos F.; Gomes, Ligia R.; Santos, Luís M. N. B. F.; Low, John NicolsonIn the title mol-ecule, C(24)H(14)N(2), the exterior C-C-C angle of the naphthalene ring system involving the two phenyl-substituted C atoms is 126.06 (11)° and the dihedral angles between the mean plane of the naphthalene ring system and those of the benzene rings are 66.63 (5) and 67.89 (5)°. In the crystal, mol-ecules are linked into a ladders by four weak C-H⋯π inter-actions.
- Acid/Base Properties of β-Blockers and Benzodiazepines in Sodium Dodecyl Sulfate Micelles. A Spectrophotometric and Potentiometric StudyPublication . de Castro, Baltazar; Gameiro, Paula; Guimarães, Carla; Lima, José L.F.C.; Reis, SaletteThe effect of sodium dodecyl sulfate (SDS) micelles on the acid-base properties of two family of pharmaceutical drugs (beta-blockers and benzodiazepines) at 25 degrees C and I = 0.1 M NaCl have been studied. The characterization of the several solution equilibria for the system drug/SDS micelle solution was performed by potentiometry and spectrophotometry, below and above the critical micelle concentration (cmc). Two widely used models have been applied to quantify the effect of micelles on the pKa of the drugs, and the results obtained point to different interactions of each family of drugs with the micelles.
- Acne vulgaris topical therapies: application of probiotics as a new prevention strategyPublication . Dapkevicius, Ieva; Romualdo, Vânia; Marques, Ana Camila; Lopes, Carla Martins; Amaral, Maria HelenaThe skin microbiome is an essential barrier for preventing the invasion of pathogens and regulating the immune responses. When this barrier is disrupted, several dermatoses, including acne vulgaris, may arise. Most people will experience acne starting at the onset of puberty and continuing into adolescence; a significant percentage of those individuals continue to suffer from it into adulthood. Although common, this dermatosis usually has an enormous impact on the self-esteem and quality of life of individuals who suffer from it. An increase in consumer literacy regarding skincare leads buyers to seek out innovative products containing ingredients with proven benefits for their concerns. Probiotics have proven to be an alternative to the use of antibiotics, often associated with undesirable effects, in the treatment and prevention of dermatological disorders such as acne. This review provides a comprehensive analysis of the pathophysiology, risk factors, symptoms, conventional treatment recommendations and main studies emphasizing innovative topical products for acne-prone skin based on probiotics. In addition, the potential advantages, and limitations/challenges associated with the implementation and manufacturing of these innovative skin products are also highlighted.
- Adipokine gene single-nucleotide polymorphisms in portuguese obese adolescents: associations with plasma concentrations of adiponectin, resistin, IL-6, IL-1β, and TNF-αPublication . Nascimento, Henrique; Vieira, Emília; Coimbra, Susana; Catarino, Cristina; Costa, Elísio; Bronze-da-Rocha, Elsa; Rocha-Pereira, Petronila; Carvalho, Márcia; Mansilha, Helena Ferreira; Rêgo, Carla; Santos, Rosário dos; Santos-Silva, Alice; Belo, LuísBackground: The genetic contribution to obesity and to circulating adipokine levels has not been completely clarified. We aimed to evaluate adipokine genes' single-nucleotide polymorphism (SNP) prevalence and its association with circulating adipokine levels and risk factors for cardiovascular disease in an obese Portuguese pediatric population. Methods: Two hundred forty-eight obese adolescents (mean age 13.4 years old; 47.2% females) participated in a cohort study. We screened 12 SNPs by direct sequencing in five adipokine genes: adiponectin (ADIPOQ: rs16861194, rs17300539, rs266729, rs2241766, rs1501299), interleukin-1β (IL-1β; rs1143627), IL-6 (IL-6; rs1800795), tumor necrosis factor-α (TNF-α; rs1800629), and resistin (RETN; rs1862513, rs3219177, rs3745367, rs3745368). Biochemical analysis included determination of circulating adipokines, C-reactive protein (CRP) levels, lipid profile, and markers of insulin resistance. Results: Compared to males, females presented higher circulating levels of insulin, adiponectin, IL-6, resistin, and leptin concentrations, but lower TNF-α levels. No statistically significant differences were found for genotype or allelic distributions between genders. In the whole sample population, adiponectin levels were influenced by ADIPOQ rs17300539 (c.-1138G>A; lower in subjects with GG genotype). When only males were considered, IL-1β, IL-6, and TNF-α levels were associated with ADIPOQ rs1501299 (c.214 + 62G>T; higher in GG subjects). TNF-α concentrations were modulated by TNF-αrs1800629 (c.-488G>A; lower in GG males), RETN rs1862513 (c.-216C>G; higher in CC subjects), and RETN rs3219177 (c.118 + 39C>T; higher in CC subjects). Leptin levels were influenced by IL-1β rs1143627 (c.-118C>T) presenting TT individuals' lower levels. Conclusions: Our data demonstrate that in pediatric obese patients, some adipokine gene SNPs have an association with circulating adipokine levels and lipid profile.
- Adrenaline and reactive oxygen species elicit proteome and energetic metabolism modifications in freshly isolated rat cardiomyocytesPublication . Costa, Vera Marisa; Silva, Renata; Tavares, Ludgero Canário; Vitorino, Rui; Amado, Francisco; Carvalho, Félix; Bastos, Maria de Lourdes; Carvalho, Márcia; Carvalho, Rui Albuquerque; Remião, FernandoThe sustained elevation of plasma and interstitial catecholamine levels, namely adrenaline (ADR), and the generation of reactive oxygen species (ROS) are well recognized hallmarks of several cardiopathologic conditions, like cardiac ischemia/reperfusion (I/R) and heart failure (HF). The present work aimed to investigate the proteomics and energetic metabolism of cardiomyocytes incubated with ADR and/or ROS. To mimic pathologic conditions, freshly isolated calcium-tolerant cardiomyocytes from adult rat were incubated with ADR alone or in the presence of a system capable of generating ROS [(xanthine with xanthine oxidase) (XXO)]. Two-dimensional electrophoresis with matrix-assisted laser desorption/ionization and time-of-flight mass spectrometer analysis were used to define protein spot alterations in the cardiomyocytes incubated with ADR and/or ROS. Moreover, the energetic metabolism and the activity of mitochondrial complexes were evaluated by nuclear magnetic resonance and spectrophotometric determinations, respectively. The protein extract was mainly constituted by cardiac mitochondrial proteins and the alterations found were included in five functional classes: (i) structural proteins, notably myosin light chain-2; (ii) redox regulation proteins, in particular superoxide dismutase (SOD); (iii) energetic metabolism proteins, encompassing ATP synthase alpha chain and dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex; (iv) stress response proteins, like the heat shock proteins; and (v) regulatory proteins, like cytochrome c and voltage-dependent anion channel 1. The XXO system elicited alterations in cardiac contractile proteins, as they showed high levels of cleavage, and also altered energetic metabolism, through increased lactate and alanine levels. The cardiomyocytes incubation with ADR resulted in an accentuated increase in mitochondrial complexes activity and the decrease in alanine/lactate ratio, thus reflecting a high cytosolic NADH/NAD(+) ratio. Furthermore, an increase in manganese SOD expression and total SOD activity occurred in the ADR group, as the increase in the mitochondrial complexes presumably led to higher 'electron leakage'. The modifications in proteins, enzymes activity, and energetic metabolism were indicative that different pathways are activated by catecholamines and ROS. These alterations altogether determine the I/R and HF specific features and contribute for the initiation or aggravation of those cardiopathologic conditions.
- Adrenaline in pro-oxidant conditions elicits intracellular survival pathways in isolated rat cardiomyocytesPublication . Costa, Vera Marisa; Silva, Renata; Ferreira, Rita; Amado, Francisco; Carvalho, Félix; Bastos, Maria de Lourdes; Carvalho, Rui Albuquerque; Carvalho, Márcia; Remião, FernandoIn several pathologic conditions, like cardiac ischemia/reperfusion, the sustained elevation of plasma and interstitial catecholamine levels, namely adrenaline (ADR), and the generation of reactive oxygen species (ROS) are hallmarks. The present work aimed to investigate in cardiomyocytes which intracellular signalling pathways are altered by ADR redox ability. To mimic pathologic conditions, freshly isolated calcium tolerant cardiomyocytes from adult rat were incubated with ADR alone or in the presence of a system capable of generating ROS [(xanthine with xanthine oxidase) (X/XO)]. ADR elicited a pro-oxidant signal with generation of reactive species, which was largely magnified by the ROS generating system. However, no change in cardiomyocytes viability was observed. The pro-oxidant signal promoted the translocation to the nucleus of the transcription factors, Heat shock factor-1 (HSF-1) and Nuclear factor-kappaB (NF-kappaB). In addition, proteasome activity was compromised in the experimental groups where the generation of reactive species occurred. The decrease in the proteasome activity of the ADR group resulted from its redox sensitivity, since the activity was recovered by adding the ROS scavenger, tiron. Proteasome inhibition seemed to elicit an increase in HSP70 levels. Furthermore, retention of mitochondrial cytochrome c and inhibition of caspase 3 activity were observed by X/XO incubation in presence or absence of ADR. In conclusion, in spite of all the insults inflicted to the cardiomyocytes, they were capable to activate intracellular responses that enabled their survival. These mechanisms, namely the pathways altered by catecholamine proteasome inhibition, should be further characterized, as they could be of relevance in the ischemia preconditioning and the reperfusion injury.