Vanadium and Melanoma: A systematic review

The application of metals in biological systems has been a rapidly growing branch of science. Vanadium has been investigated and reported as an anticancer agent. Melanoma is the most aggressive type of skin cancer, the incidence of which has been increasing annually worldwide. It is of paramount importance to identify novel pharmacological agents for melanoma treatment. Herein, a systematic review of publications including “Melanoma and Vanadium” was performed. Nine vanadium articles in several melanoma cells lines such as human A375, human CN-mel and murine B16F10, as well as in vivo studies, are described. Vanadium-based compounds with anticancer activity against melanoma include: (1) oxidovanadium(IV); (2) XMenes; (3) vanadium pentoxide, (4) oxidovanadium(IV) pyridinonate compounds; (5) vanadate; (6) polysaccharides vanadium(IV/V) complexes; (7) mixed-metal binuclear ruthenium(II)–vanadium(IV) complexes; (8) pyridoxal-based oxidovanadium(IV) complexes and (9) functionalized nanoparticles of yttrium vanadate doped with europium. Vanadium compounds and/or vanadium materials show potential anticancer activities that may be used as a useful approach to treat melanoma.UIDB/04326/2020info:eu-repo/semantics/publishedVersio

Characterization of potential intoxications with medicines in a regional setting

The 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.info:eu-repo/semantics/publishedVersio

Tribbles pseudokinases in colorectal cancer

The 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.Project TRIBBLES–748585 e Fundação para a Ciência e a Tecnologia (FCT) (PTDC/MEDONC/4167/2020 “ENDURING”)info:eu-repo/semantics/publishedVersio

Avaliação do potencial das Tiazolidinedionas como estratégia terapêutica no Melanoma

O 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.info:eu-repo/semantics/publishedVersio

Laxative use by community pharmacy users in southern Portugal

Publicação sob a forma de PosterThe 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.info:eu-repo/semantics/publishedVersio

Tribbles gene expression profiles in colorectal cancer

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death due to cancer in the world. Therefore, the identification of novel druggable targets is urgently needed. Tribbles proteins belong to a pseudokinase family, previously recognized in CRC as oncogenes and potential therapeutic targets. Here, we analyzed the expression of TRIB1, TRIB2, and TRIB3 simultaneously in 33 data sets from CRC based on available GEO profiles. We show that all three Tribbles genes are overrepresented in CRC cell lines and primary tumors, though depending on specific features of the CRC samples. Higher expression of TRIB2 in the tumor microenvironment and TRIB3 overexpression in an early stage of CRC development, unveil a potential and unexplored role for these proteins in the context of CRC. Differential Tribbles expression was also explored in diverse cellular experimental conditions where either genetic or pharmacological approaches were used, providing novel hints for future research. This comprehensive bioinformatic analysis provides new insights into Tribbles gene expression and transcript regulation in CRC.info:eu-repo/semantics/publishedVersio

Biological consequences of Vanadium effects on formation of reactive oxygen species and lipid peroxidation

Lipid peroxidation (LPO), a process that affects human health, can be induced by exposure to vanadium salts and compounds. LPO is often exacerbated by oxidation stress, with some forms of vanadium providing protective effects. The LPO reaction involves the oxidation of the alkene bonds, primarily in polyunsaturated fatty acids, in a chain reaction to form radical and reactive oxygen species (ROS). LPO reactions typically affect cellular membranes through direct effects on membrane structure and function as well as impacting other cellular functions due to increases in ROS. Although LPO effects on mitochondrial function have been studied in detail, other cellular components and organelles are affected. Because vanadium salts and complexes can induce ROS formation both directly and indirectly, the study of LPO arising from increased ROS should include investigations of both processes. This is made more challenging by the range of vanadium species that exist under physiological conditions and the diverse effects of these species. Thus, complex vanadium chemistry requires speciation studies of vanadium to evaluate the direct and indirect effects of the various species that are present during vanadium exposure. Undoubtedly, speciation is important in assessing how vanadium exerts effects in biological systems and is likely the underlying cause for some of the beneficial effects reported in cancerous, diabetic, neurodegenerative conditions and other diseased tissues impacted by LPO processes. Speciation of vanadium, together with investigations of ROS and LPO, should be considered in future biological studies evaluating vanadium effects on the formation of ROS and on LPO in cells, tissues, and organisms as discussed in this review.info:eu-repo/semantics/publishedVersio

FOXO1 represses PPARα-Mediated induction of FGF21 gene expression

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/).info:eu-repo/semantics/publishedVersio

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance.

Therapy 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.This work was supported by the FUNDAÇÃO PARA A CIÊNCIA E TECNOLOGIA (FCT) Research Center Grant UID/BIM/04773/2013, Centre for Biomedical Research (CBMR), and by the Spanish Ministry of Science, Innovation and Universities through Grant RTI2018-094629-B-I00 to WL. B.I.F. was supported by FCT-SFRH/BPD/100434/2014 and the Marie Curie Individual Fellowship project TRIBBLES (#748585). This work was also supported by two LPCC-NRS/Terry Fox grants (2016/2017; 2017/2018). S. Machado is the recipient of a ProRegeM grant PD/BD/114258/2016. I. Duarte was supported by a scholarship from FCT Grant PTDC/BEX-BID/5410/2014S