Antioxidants as stabilizers of UV filters: an example for the UV-B filter octylmethoxycinnamate

Background: Sunlight is one of the main harmful exogenous factors that induce the reactive oxygen species formation. The human skin is the first line of photoprotection against harmful exogenous factors, such as UV radiations. The topical application of sunscreens, containing UV-B filters, is widely used to protect against UV-induced damage. Octylmethoxycinnamate is the world’s most widely used UV-B filter in sunscreens. However, recent studies have demonstrated that this substance is an endocrine disruptor compound and with potential to damage DNA. Thus, the safety of this organic filter is a current concern for human health, and it was urgent to develop new photoprotective strategies. In this sense, due to the potential to neutralize the UV-induced free radicals, the use of antioxidants as UV filter stabilizers presented as a novel promising strategy. Research: The purpose of this review was to assess the use of antioxidants as stabilizers for UV-B filter octylmethoxycinnamate. For this, we discuss the chemical and physical characteristics of UV-B filter octylmethoxycinnamate, emphasizing the stability, photostability, and reactivity of this UV filter. The use of antioxidants in sunscreens will also be addressed, from a perspective of the main characteristics that allowed their use in sunscreen formulations. Then, the concomitant use of both was described from a historical and physical chemical perspective, always emphasizing the advantages and disadvantages of this association. Conclusions: The combination of antioxidants with UV-B filter octylmethoxycinnamate in appropriated formulations represents a viable strategy to protect the human skin against UV-induced damage.UBI-Santander Totta (BID/FCS/2018)info:eu-repo/semantics/publishedVersio

Potassium channels are involved in testosterone-induced vasorelaxation of human umbilical artery

Recent studies have shown that testosterone induces relaxation of different arteries, although the mechanism of this action is still under debate. We investigated the involvement of potassium channels in this mechanism. Using standard organ bath techniques, rings of human umbilical arteries (HUA) without endothelium were contracted by serotonin (5-HT, 1 μM), histamine (10 μM) and potassium chloride (KCl, 30 and 60 mM), and the vasorelaxant effect of testosterone was analysed. Testosterone (100 μM) relaxed human umbilical arteries contracted with 5-HT (30.1±3.2%), histamine (55.1±2.6%), KCl 30 mM (52.9±8.3%) and KCl 60 mM (54.8±6.3%). Flutamide (10 μM), an inhibitor of classical intracellular testosterone receptor, and glibenclamide, an ATP-sensitive potassium-channels (KATP) inhibitor, did not influence the testosterone relaxant effect. 4-aminopyridine, a voltagesensitive potassium-channels (Kv) inhibitor, decreased the effect of testosterone on histamine- and 5-HT-contracted arteries. Tetraethylammonium (TEA), which inhibits Kv channels and large-conductance Ca2+-activated potassium channels (BKCa), decreased the effect of testosterone on KCl (60 mM)-contracted and 5-HT-contracted HUA. In conclusion, testosterone induces relaxation of HUA, and this effect does not appear to be mediated via a classic intracellular testosterone receptor-dependent mechanism. Our results suggest that this relaxation is partially mediated by activation of BKCa and KV channels. The involvement of these two channels in testosterone-relaxant mechanism is dependent on the pathways activated by the contractile agent used

Vascular Pathways of Testosterone: Clinical Implications

Cardiovascular diseases (CVD) are one of the leading causes of death worldwide. Testosterone (T) is an important sex hormone that triggers several genomic and non-genomic pathways, leading to improvements of several cardiovascular risk factors and quality of life in men. At the vascular level, the key effect of T is the vasorelaxation. This review discusses the molecular pathways and clinical implications of T in the vascular system. Firstly, the mechanisms involved in the T vasodilator effect will be presented. Then, it will be discussed the association of T with the main risks for CVD, namely metabolic syndrome, type 2 diabetes mellitus, obesity, atherosclerosis, dyslipidaemia and hypertension. Several studies have shown a correlation between low T levels and an increased prevalence of several CVD. These observations suggest that T has beneficial effects on the cardiovascular system and that testosterone replacement therapy may become a therapeutic reality for some of these disorders.UBI-Santander Totta (BID/FCS/2018)info:eu-repo/semantics/publishedVersio

PDE4 and PDE5 regulate cyclic nucleotides relaxing effects in human umbilical arteries

Cyclic nucleotides (cAMP and cGMP) are the main second messengers linked to vasodilatation. They are synthesized by cyclases and degraded by different types of phosphodiesterases (PDE). The effect of PDE inhibition and cyclases stimulation on 5-hydroxytryptamine (5-HT; 1 microM) and histamine (10 microM) contracted arteries was analysed. Stimulation of guanylate cyclase or adenylate cyclase relaxed the histamine- and 5-HT-induced contractions indicating that intracellular increase of cyclic nucleotides leads to vasodilatation of the human umbilical artery. We investigated the role of different PDE families in the regulation of this effect. The presence of the different PDE types in human umbilical artery smooth muscle was analysed by RT-PCR and the expression of PDE1B, PDE3A, PDE3B, PDE4C, PDE4D and PDE5A was detected. The unspecific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX; 50 microM) relaxed histamine-contracted human umbilical artery on 47.4+/-7.2%. This effect seems to be due to PDE4 and PDE5 inhibition because among the selective PDE inhibitors used only the PDE4 inhibitor (rolipram; 1 microM) and the PDE5 inhibitors (dipyridamole and T0156; 3 microM and 1 microM respectively) induced significant relaxation (39.0+/-8.7, 30.4+/-6.0 and 36.3+/-2.8 respectively). IBMX, dipyridamole and T0156 produced similar relaxation on 5-HT-induced contraction. After forskolin, the addition of IBMX or rolipram increased the effect of the adenylate cyclase stimulator and almost completely relaxed the human umbilical artery contracted by histamine (92.5+/-4.9 and 90.9+/-4.7 respectively), suggesting a main role of PDE4. The data obtained with 5-HT contracted arteries confirmed this, because only rolipram and IBMX significantly increased the forskolin vasodilator effect. The administration of dipyridamole and T0156 after sodium nitroprusside (SNP) induced a significant increase of the SNP relaxant effect on histamine-contracted arteries, but PDE1 and PDE3 inhibition did not increase the effect of the guanylate cyclase stimulator. Similar effects were obtained in 5-HT contracted arteries, the SNP induced relaxation was increased by the PDE5 inhibition, but not by PDE1 or PDE3 inhibition. In summary, our results demonstrate that: 1) the increase of cAMP and/or cGMP levels induces relaxation of the human umbilical vascular smooth muscle; 2) four families of PDE are expressed in this smooth muscle: PDE1, PDE3, PDE4 and PDE5; 3) between these families, PDE4 and PDE5 are the key enzymes involved in the regulation of the relaxation associated to cAMP and cGMP, respectively

Triiodothyronine modulates neuronal plasticity mechanisms to enhance functional outcome after stroke

The development of new therapeutic approaches for stroke patients requires a detailed understanding of the mechanisms that enhance recovery of lost neurological functions. The efficacy to enhance homeostatic mechanisms during the first weeks after stroke will influence functional outcome. Thyroid hormones (TH) are essential regulators of neuronal plasticity, however, their role in recovery related mechanisms of neuronal plasticity after stroke remains unknown. This study addresses important findings of 3,5,3'-triiodo-L-thyronine (T3) in the regulation of homeostatic mechanisms that adjust excitability - inhibition ratio in the post-ischemic brain. This is valid during the first 2 weeks after experimental stroke induced by photothrombosis (PT) and in cultured neurons subjected to an in vitro model of acute cerebral ischemia. In the human post-stroke brain, we assessed the expression pattern of TH receptors (TR) protein levels, important for mediating T3 actions.Our results show that T3 modulates several plasticity mechanisms that may operate on different temporal and spatial scales as compensatory mechanisms to assure appropriate synaptic neurotransmission. We have shown in vivo that long-term administration of T3 after PT significantly (1) enhances lost sensorimotor function; (2) increases levels of synaptotagmin 1&2 and levels of the post-synaptic GluR2 subunit in AMPA receptors in the peri-infarct area; (3) increases dendritic spine density in the peri-infarct and contralateral region and (4) decreases tonic GABAergic signaling in the peri-infarct area by a reduced number of parvalbumin+ / c-fos+ neurons and glutamic acid decarboxylase 65/67 levels. In addition, we have shown that T3 modulates in vitro neuron membrane properties with the balance of inward glutamate ligand-gated channels currents and decreases synaptotagmin levels in conditions of deprived oxygen and glucose. Interestingly, we found increased levels of TRβ1 in the infarct core of post-mortem human stroke patients, which mediate T3 actions. Summarizing, our data identify T3 as a potential key therapeutic agent to enhance recovery of lost neurological functions after ischemic stroke.info:eu-repo/semantics/publishedVersio

Fucus spp. (Phaeophyceae, Heterokontophyta) como indicador de contaminação ambiental

Mestrado em ToxicologiaO género Fucus apresenta vasta distribuição na zona costeira Ibérica, tendo sido descritas cinco espécies para Espanha e quatro para Portugal (Fucus spiralis L., F. vesiculosus L., F. ceranoides L. e F. serratus L.). Possui enorme importância, tanto ecológica como comercial, essencialmente na produção de produtosnaturais medicinais. As espécies deste género surgem em diversos locais, incluindo os expostos a descargas de efluentes urbanos, industriais e aos lixíviados de terrenos agrícolas, encontrando-se normalmente nas zonas rochosas, onde sofrem zonação notória, que é controlada por complexas interacções fisiológicas e biológicas. O objectivo principal deste trabalho consistiu em efectuar os estudos de base necessários à utilização de espécies do género Fucus como bioindicadores em programas de biomonitorização em zonas costeiras e estuarinas da costa Noroeste de Portugal. Para atingir este objectivo foram desenvolvidos três trabalhos específicos: 1) analisar a variação morfológica de três espécies de Fucus (F. ceranoides, F. spiralis e F. vesiculosus), recolhidos na costa Noroeste Atlântica de Portugal entre o estuário do rio Minho e a Ria de Aveiro durante um ano, e o estabelecimento de correlações com os parâmetros ambientais; 2) avaliar o potencial de bioacumulação de mercúrio das espécies de Fucus [F. ceranoides, F. spiralis (F. spiralis var. platycarpus e F. spiralis var. spiralis) e F. vesiculosus]; 3) desenvolver e validar a metodologia necessária à utilização da actividade de glutationa S-transferase (GST) de Fucus spp. como biomarcador de contaminação ambiental. Através da Análise Canónica de correspondência foi possível perceber que o factor ambiental preponderante na variação dos parâmetros morfométricos parece ser a temperatura, estando este intimamente relacionado com o pH e a salinidade, em todas as espécies analisadas. A quantificação de mercúrio em três partes estruturais (receptáculos, lâmina e base) das espécies de Fucus, permitiu observar que os receptáculos continham menor concentração do que a base e a lâmina. Os valores obtidos para o sedimento apresentaram-se concordantes com os obtidos no material biológico (apesar dos espécimes consistentemente registarem concentrações superiores). Estes resultados sugerem que as espécies e variedades de Fucus estudadas são boas bioindicadores da contaminaçãopor mercúrio, em ecossistemas marinhos e estuarinos. F. ceranoides, F. spiralis var. platycarpus e F. vesiculosus apresentaram os valores mais baixos da actividade da GST nos locais de referência. As estações de amostragem, localizadas em áreas com reconhecida contaminação por hidrocarbonetos aromáticos policíclicos (HAPs), apresentaram valores mais elevados de actividade de GST, sugerindo indução dos mecanismos de destoxificação. Este facto não foi, no entanto, observado em F. spiralis var. spiralis.The genus Fucusexhibits a wide distribution on the Iberian coast. Five species have been described for Spain and four for Portugal (Fucus spiralis L., F. vesiculosus L., F. ceranoides L. and F. serratus L.). This genus is of enormous importance, both from ecological and commercial (essentially in the production of natural medicinal products) points of view. Fucus spp. exists in several sites, including those receiving urban and industrial effluent discharges and leachates from farmland. The species of the Fucus genus are mainly found in rocky areas, where conspicuous zonation occurs, which is controlled by complex physiological and biological interactions. The main aim of this study was to launch the necessary basis to validate the use of the Fucusspecies as bioindicators in coastal and estuarine environments. To achieve this objective three steps with specific objectives were outlined: 1) analysis of morphologic variation in three species of Fucus (F. ceranoides, F. spiralis and F. vesiculosus), collected during a year, from the Portuguese Northwestern Atlantic coast (between the estuary of Minho river and the Aveiro tidal lagoon), and the establishment of correlations with environmental parameters; 2) evaluation of the potential of Fucus [F. ceranoides, F. spiralis (F. spiralis var. platycarpus and F. spiralis var. spiralis) and F. vesiculosus] to bioacumulate mercury; 3) to develop and validate the necessary methodologies for the application of Fucus spp. glutatione S-transferase as a biomarker of environmental contamination. Canonical correspondence analysis indicates that the dominant factor influencing morphometric parameters is temperature, always in close correlation with pH and salinity. Quantification of mercury in the three structural parts considered (receptacles, stipe and holdfast) showed that the receptacles consistently showed the lowest concentrations throughout the entire sampling campaign. Values obtained for the sediment were always consistent with the ones obtained for specimens, (the latter always presented higher concentrations). This leads to the conclusion that Fucuscan be considered a good bioindicator for mercury contamination in coastal and estuarine environments. As expected, F. ceranoides, F. spiralis var. platycarpus and F. vesiculosus registered the lowest values of GST activity in the reference stations. Sampling stations located in areas were contamination by polycyclic aromatic hydrocarbons (PAHs) is well known, showed higher values of activity for this enzyme, suggesting that detoxification mechanisms were induced.However, a different pattern was observed for F. spiralis var. spiralis

Pre-Eclampsia and Eclampsia: An Update on the Pharmacological Treatment Applied in Portugal

Pre-eclampsia and eclampsia are two hypertensive disorders of pregnancy, considered major causes of maternal and perinatal death worldwide. Pre-eclampsia is a multisystemic disease characterized by the development of hypertension after 20 weeks of gestation, with the presence of proteinuria or, in its absence, of signs or symptoms indicative of target organ injury. Eclampsia represents the consequence of brain injuries caused by pre-eclampsia. The correct diagnosis and classification of the disease are essential, since the therapies for the mild and severe forms of pre-eclampsia are different. Thus, this review aims to describe the most advisable antepartum pharmacotherapy for pre-eclampsia and eclampsia applied in Portugal and based on several national and international available guidelines. Slow-release nifedipine is the most recommended drug for mild pre-eclampsia, and labetalol is the drug of choice for the severe form of the disease. Magnesium sulfate is used to prevent seizures caused by eclampsia. Corticosteroids are used for fetal lung maturation. Overall, the pharmacological prevention of these diseases is limited to low-dose aspirin, so it is important to establish the safest and most effective available treatment

Vascular mechanisms of testosterone: the non-genomic point of view

Testosterone (T) is the predominant endogenous androgen in the bloodstream. At the vascular level, T presents genomic and non-genomic effects, and both effects may overlap. The genomic actions assume that androgens can freely cross the plasma membrane of target cells and bind to nuclear androgen receptors, inducing gene transcription and protein synthesis. The non-genomic effects have a more rapid onset and may be related to the interaction with protein/receptor/ion channels of the plasma membrane. The key T effect at the vascular level is vasorelaxation, which is primarily due to its rapid effect. Thus, the main purpose of this review is to discuss the T non-genomic effects at the vascular level and the molecular pathways involved in its vasodilator effect observed in in vivo and in vitro studies. In this sense, the nuclear receptor activation, the influence of vascular endothelium and the activation or inhibition of ion channels (potassium and calcium channels, respectively) will be reviewed regarding all the data that corroborated or not. Moreover, this review also provides a brief update on the association of T with the risk factors for cardiovascular diseases, namely metabolic syndrome, type 2 diabetes mellitus, obesity, atherosclerosis, dyslipidaemia, and hypertension. In summary, in this paper we consider the non-genomic vascular mode of action of androgen in physiological conditions and the main risk factors for cardiovascular diseases.info:eu-repo/semantics/publishedVersio

Regulation of human umbilical artery contractility by different serotonin and histamine receptors

We studied the role of several serotonin (5-HT) and histamine receptors in the regulation of human umbilical artery (HUA) contractility. Among the 5-HT agonists used, only the 5-HT2A and 5HT1B/D agonists contracts HUA. The 5-HT-induced contractions were fully inhibited by ketanserin (5-HT2A antagonist). The 5-HT7-activation also relaxes and increases intracellular cyclic adenosine monophosphate (cAMP). Among the histamine receptor agonists, only betahistine (H1 agonist) induced significant contractile effect. Histamine-induced contraction was partially relaxed by pyrilamine (H1 antagonist). Betahistine-induced contraction was partially blocked by dimaprit (H2 agonist) and by the H3 agonist when a low concentration of forskolin is present. Both, H2 and H3 agonists increased the cAMP intracellular levels in HUA smooth muscle. These findings show that in HUA, 5-HT2A- and 5-HT1B/1D-activation lead to vasoconstriction and 5-HT7-activation induces vasorelaxation. Concerning histamine receptors, H1-activation induces contraction and H2- and H 3-activation lead to vasorelaxation

17 Beta-Estradiol and progesterone inhibit L-type Ca2+ current of rat aorta smooth muscle cells

Sex hormones like 17ß-estradiol (ßES) and progesterone have shown rapid non-genomic vasodilator effects, which could be involved in the protection of cardiovascular system. However, the precise mechanism by which this effect occurs has not been elucidated yet, even if Ca2+ influx inhibition seems to be implicated. The aim of this study was to study the influence of ßES and progesterone on the L-type Ca2+ current measured by whole cell voltage-clamp in A7r5 cells. Voltage-operated Ca2+ currents were elicited by square-step voltage pulses and pharmacologically characterized as L-type currents by (-)-Bay K8644 (BAY) and nifedipine. Both ßES and progesterone (1-100 µM), rapidly and reversibly inhibited, in a concentration dependent manner, either non-stimulated or BAY-stimulated Ca2+ currents registered in A7r5 cells. These results suggest that ßES and progesterone inhibit L-type voltage-operated Ca2+ channels through a non-genomic pathway. Consequently, these hormones inhibit the Ca2+ entry into smooth muscle cells from rat aorta, an effect that can contribute for the protection of the cardiovascular system