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- Decavanadate and metformin-decavanadate effects in human melanoma cellsPublication . de Sousa-Coelho, Ana Luísa; Aureliano, Manuel; Fraqueza, Gil; Serrão, Gisela; Gonçalves, João; Sánchez-Lombardo, Irma; Link, Wolfgang; Ferreira, BibianaDecavanadate is a polyoxometalate (POMs) that has shown extensive biological activities, including antidiabetic and anticancer activity. Importantly, vanadium-based compounds as well as antidiabetic biguanide drugs, such as metformin, have shown to exert therapeutic effects in melanoma. A combination of these agents, the metformin-decavanadate complex, was also recognized for its antidiabetic effects and recently described as a better treatment than the monotherapy with metformin enabling lower dosage in rodent models of diabetes. Herein, we compare the effects of decavanadate and metformin-decavanadate on Ca2+-ATPase activity in sarcoplasmic reticulum vesicles from rabbit skeletal muscles and on cell signaling events and viability in human melanoma cells. We show that unlike the decavanadate-mediated non-competitive mechanism, metformin-decavanadate inhibits Ca2+-ATPase by a mixed-type competitive-non-competitive inhibition with an IC50 value about 6 times higher (87 mu M) than the previously described for decavanadate (15 mu M). We also found that both decavanadate and metformin-decavanadate exert antiproliferative effects on melanoma cells at 10 times lower concentrations than monomeric vanadate. Western blot analysis revealed that both, decavanadate and metformin-decavanadate increased phosphorylation of extracellular signal-regulated kinase (ERK) and serine/ threonine protein kinase AKT signaling proteins upon 24 h drug exposure, suggesting that the anti-proliferative activities of these compounds act independent of growth-factor signaling pathways.
- Avaliação do potencial das Tiazolidinedionas como estratégia terapêutica no MelanomaPublication . Espírito Santo, Margarida; De Sousa-Coelho, Ana Luísa; Ana Patrícia, PintoO melanoma é uma doença mundial que representa a forma mais agressiva de cancro da pele com incidência e mortalidade em contínuo aumento. Apesar de existirem terapêuticas direcionadas às mutações específicas no melanoma, a resistência adquirida pelos doentes ao tratamento constitui uma barreira ao sucesso da terapêutica, suscitando assim a necessidade de identificação de novos fármacos e novas opções terapêuticas. Nos últimos anos tem surgido grande interesse na potencial utilização de antidiabéticos orais, como a metformina (biguanida) no tratamento do melanoma. As tiazolidinedionas (TZDs), agonistas do receptor PPARγ, são também uma classe de fármacos utilizados no tratamento da diabetes tipo 2.
- FOXO1 represses PPARα-Mediated induction of FGF21 gene expressionPublication . De Sousa-Coelho, Ana Luísa; Gacias, Mar; O'Neill, Brian T.; Relat, Joana; Link, Wolfgang; Haro, Diego; Marrero, Pedro F.Fibroblast growth factor 21 (FGF21) has emerged as a metabolic regulator that exerts potent anti-diabetic and lipid-lowering effects in animal models of obesity and type 2 diabetes, showing a protective role in fatty liver disease and hepatocellular carcinoma progression. Hepatic expression of FGF21 is regulated by PPARa and is induced by fasting. Ablation of FoxO1 in liver has been shown to increase FGF21 expression in hyperglycemia. To better understand the role of FOXO1 in the regulation of FGF21 expression we have modified HepG2 human hepatoma cells to overexpress FoxO1 and PPARa. Here we show that FoxO1 represses PPARa-mediated FGF21 induction, and that the repression acts on the FGF21 gene promoter without affecting other PPARa target genes. Additionally, we demonstrate that FoxO1 physically interacts with PPARa and that FoxO1/3/4 depletion in skeletal muscle contributes to increased Fgf21 tissue levels. Taken together, these data indicate that FOXO1 is a PPARa-interacting protein that antagonizes PPARa activity on the FGF21 promoter. Because other PPARa target genes remained unaffected, these results suggest a highly specific mechanism implicated in FGF21 regulation. We conclude that FGF21 can be specifically modulated by FOXO1 in a PPARa-dependent manner. (c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
- Characterization of potential intoxications with medicines in a regional settingPublication . Nascimento, Tânia; Santos, Teresa; Rato, Fátima; De Sousa-Coelho, Ana LuísaThe Portuguese Poison Information Center (from Portuguese—CIAV) is a call center that offers medical assistance in case of possible intoxication with any kind of product, including medicines. This center´s main goal is to inform and guide the general public and health professionals. This work aimed to analyze and compare data corresponding to the telephone calls from the Algarve region (South of Portugal), received by CIAV during 2019 and 2020, regarding potential intoxications with medicines. To this end, data provided by CIAV on possible cases of medication intoxication in the Algarve region were collected, including the number of calls received, the place of origin of the call, the age group and sex of the intoxicated individual, the route of exposure to the drug, the circumstances of contact with the substance, the existence of symptoms, and the drug or drugs involved in the potential intoxication. The results showed that the number of cases slightly decreased in 2020 (n = 1261) compared with 2019 (n = 1340), with a high number of cases of intoxication in children between one and four years old in both years (21.2%; n = 152 in 2019; 16.4%; n = 115 in 2020). The drugs belonging to the locomotor system group (paracetamol and ibuprofen) were the main drugs involved, followed by the central nervous system pharmacotherapeutic group, namely benzodiazepines (diazepam and alprazolam). Paracetamol was the main drug responsible for the calls to CIAV (n = 71 in 2019; n = 63 in 2020), while for the remaining drugs there were fluctuations in their positions between both years. In some cases, this swinging may be explained by the possible changes in therapy due to potential interactions with drugs used for the treatment of symptoms of COVID-19 or perhaps related to misleading information released by the media about the use of some drugs, such as ibuprofen, during lockdown periods. Although there has been a decrease in calls to report possible drug intoxication in the Algarve region, the profile of calls was very similar. Paracetamol was the drug with the highest number of reported cases and the group of psychotropic drugs showed the largest increase between 2019 and 2020.
- Health literacy assessment: Translation and cultural adaptation to the Portuguese populationPublication . Espírito Santo, Margarida; Nascimento, Tânia; Pinto, Ezequiel; De Sousa-Coelho, Ana Luísa; Newman, JeffHealth literacy (HL) has been widely referenced as a determinant of health outcomes, making the assessment of low HL a fundamental step to plan educational interventions. This study aimed to translate and adapt the Short Assessment of Health Literacy-Spanish and English (SAHL-S&E) questionnaire into European Portuguese.
- Skeletal muscle expression of adipose-specific phospholipase in peripheral artery diseasePublication . Parmer, Caitlin; De Sousa-Coelho, Ana Luísa; Cheng, Henry S.; Daher, Grace; Burkart, Alison; Dreyfuss, Jonathan M.; Pan, Hui; Prenner, Joshua C.; Keilson, Jessica M.; Pande, Reena; Henkin, Stanislav; Feinberg, Mark W.; Patti, Mary Elizabeth; Creager, Mark A.Flow-limiting atherosclerotic lesions of arteries supplying the limbs are a cause of symptoms in patients with peripheral artery disease (PAD). Musculoskeletal metabolic factors also contribute to the pathophysiology of claudication, which is manifest as leg discomfort that impairs walking capacity. Accordingly, we conducted a case-control study to determine whether skeletal muscle metabolic gene expression is altered in PAD. Calf skeletal muscle gene expression of patients with PAD and healthy subjects was analyzed using microarrays. The top-ranking gene differentially expressed between PAD and controls (FDR < 0.001) wasPLA2G16, which encodes adipose-specific phospholipase A2 (AdPLA) and is implicated in the maintenance of insulin sensitivity and regulation of lipid metabolism. Differential expression was confirmed by qRT-PCR;PLA2G16was downregulated by 68% in patients with PAD (p< 0.001). Expression ofPla2g16was then measured in control (db/+) and diabetic (db/db) mice that underwent unilateral femoral artery ligation. There was significantly reduced expression ofPla2g16in the ischemic leg of both control and diabetic mice (by 51%), with significantly greater magnitude of reduction in the diabetic mice (by 79%). We conclude that AdPLA is downregulated in humans with PAD and in mice with hindlimb ischemia. Reduced AdPLA may contribute to impaired walking capacity in patients with PAD via its effects on skeletal muscle metabolism. Further studies are needed to fully characterize the role of AdPLA in PAD and to investigate its potential as a therapeutic target for alleviating symptoms of claudication.
- Harmine and Piperlongumine revert TRIB2-mediated drug resistancePublication . Machado, Susana; Silva, Andreia; De Sousa-Coelho, Ana Luísa; Duarte, Isabel; Grenho, Inês; Santos, Bruno F; Mayoral-Varo, Victor; Megias, Diego; Sánchez-Cabo, Fátima; Dopazo, Ana; Ferreira, Bibiana I.; Link, WolfgangTherapy resistance is responsible for most relapses in patients with cancer and is the major challenge to improving the clinical outcome. The pseudokinase Tribbles homologue 2 (TRIB2) has been characterized as an important driver of resistance to several anti-cancer drugs, including the dual ATP-competitive PI3K and mTOR inhibitor dactolisib (BEZ235). TRIB2 promotes AKT activity, leading to the inactivation of FOXO transcription factors, which are known to mediate the cell response to antitumor drugs. To characterize the downstream events of TRIB2 activity, we analyzed the gene expression profiles of isogenic cell lines with different TRIB2 statuses by RNA sequencing. Using a connectivity map-based computational approach, we identified drug-induced gene-expression profiles that invert the TRIB2-associated expression profile. In particular, the natural alkaloids harmine and piperlongumine not only produced inverse gene expression profiles but also synergistically increased BEZ235-induced cell toxicity. Importantly, both agents promote FOXO nuclear translocation without interfering with the nuclear export machinery and induce the transcription of FOXO target genes. Our results highlight the great potential of this approach for drug repurposing and suggest that harmine and piperlongumine or similar compounds might be useful in the clinic to overcome TRIB2-mediated therapy resistance in cancer patients.
- Tribbles pseudokinases in colorectal cancerPublication . Ferreira, Bibiana; Santos, Bruno F; Link, Wolfgang; De Sousa-Coelho, Ana LuísaThe Tribbles family of pseudokinases controls a wide number of processes during cancer on-set and progression. However, the exact contribution of each of the three family members is still to be defined. Their function appears to be context-dependent as they can act as oncogenes or tumor suppressor genes. They act as scaffolds modulating the activity of several signaling pathways involved in different cellular processes. In this review, we discuss the state-of-knowledge for TRIB1, TRIB2 and TRIB3 in the development and progression of colorectal cancer. We take a perspective look at the role of Tribbles proteins as potential biomarkers and therapeutic targets. Specifically, we chronologically systematized all available articles since 2003 until 2020, for which Tribbles were associated with colorectal cancer human samples or cell lines. Herein, we discuss: (1) Tribbles amplification and overexpression; (2) the clinical significance of Tribbles overexpression; (3) upstream Tribbles gene and protein expression regulation; (4) Tribbles pharmacological modulation; (5) genetic modulation of Tribbles; and (6) downstream mechanisms regulated by Tribbles; establishing a comprehensive timeline, essential to better consolidate the current knowledge of Tribbles’ role in colorectal cancer.
- Adequação terapêutica da utilização de inibidores da bomba de protões: estudo exploratórioPublication . Espírito Santo, Margarida; De Sousa-Coelho, Ana Luísa; Duarte, Denise; Nascimento, TâniaO aumento acentuado do consumo de fármacos inibidores da bomba de protões (IBPs) que se tem verificado nos últimos cinco anos fez surgir a necessidade de analisar a sua utilização na prática clínica atual e avaliar as possíveis consequências associadas ao seu consumo. Pretendeu-se com este estudo analisar a adequação terapêutica da utilização de IBPs na prática clínica de uma farmácia comunitária.
- Laxative use by community pharmacy users in southern PortugalPublication . Lourenço, Laura; De Sousa-Coelho, Ana Luísa; Nascimento, Tânia; Assunção, Lucília; Espírito Santo, MargaridaThe aim of this study was the characterization of laxative use by Pharmacy users, including the prevalence of use, types of laxatives used, and places for acquiring and obtaining advice on laxatives. METHODS: A cross-sectional and descriptive study was carried, using a structured questionnaire, in a Community Pharmacy located in Faro, Portugal. During a period of 3 weeks, all Pharmacy users (≥18 years) who agreed to voluntarily participate in this study, were enrolled. Our study sample included 50 users, mainly women (74%), aged from 22 to 94 years (median of 59 years). RESULTS: Most of the participants (88%) reported to be suffering or to have previously suffered from constipation, whereas 62% indicated to be suffering with symptoms for more than 3 years. From those, 64% had presented symptoms of constipation more than once a week in the previous year. Whenever users felt constipated, more than half (58%) indicated to use a laxative. Contact laxatives were the more often used (63%), while 18% and 8% of the participants indicated to have used bulk-forming and osmotic laxatives, respectively, during the previous year. Over half of the participants (54%) indicated to use laxatives at least on a weekly basis, with 38% presenting a daily consumption. Elderly users, ≥60 years, were who used laxatives more often (65% daily; p<0.001). Whereas Pharmacies were the preferred place to purchase laxatives (85%), only about 40% of the users indicated to ask for health professional advise at the time of acquisition. CONCLUSIONS: A high rate and frequency of laxative use was identified in the study sample, particularly contact laxatives. It is imperative, therefore, to provide users with more information on non-pharmacological measures to avoid and approach constipation and its symptoms, as well as further information such as overuse complications, allowing the appropriate selection of the laxative. Pharmacy professionals have a key role on this area, and related education campaigns should be implemented.