The role of cGMP on adenosine A1 receptor-mediated inhibition of synaptic transmission at the hippocampus

Copyright © 2016 Pinto, Serpa, Sebastião and Cascalheira. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Both adenosine A1 receptor and cGMP inhibit synaptic transmission at the hippocampus and recently it was found that A1 receptor increased cGMP levels in hippocampus, but the role of cGMP on A1 receptor-mediated inhibition of synaptic transmission remains to be established. In the present work we investigated if blocking the NOS/sGC/cGMP/PKG pathway using nitric oxide synthase (NOS), protein kinase G (PKG), and soluble guanylyl cyclase (sGC) inhibitors modify the A1 receptor effect on synaptic transmission. Neurotransmission was evaluated by measuring the slope of field excitatory postsynaptic potentials (fEPSPs) evoked by electrical stimulation at hippocampal slices. N6-cyclopentyladenosine (CPA, 15 nM), a selective A1 receptor agonist, reversibly decreased the fEPSPs by 54 ± 5%. Incubation of the slices with an inhibitor of NOS (L-NAME, 200 μM) decreased the CPA effect on fEPSPs by 57 ± 9% in female rats. In males, ODQ (10 μM), an sGC inhibitor, decreased the CPA inhibitory effect on fEPSPs by 23 ± 6%, but only when adenosine deaminase (ADA,1 U/ml) was present; similar results were found in females, where ODQ decreased CPA-induced inhibition of fEPSP slope by 23 ± 7%. In male rats, the presence of the PKG inhibitor (KT5823, 1 nM) decreased the CPA effect by 45.0 ± 9%; similar results were obtained in females, where KT5823 caused a 32 ± 9% decrease on the CPA effect. In conclusion, the results suggest that the inhibitory action of adenosine A1 receptors on synaptic transmission at hippocampus is, in part, mediated by the NOS/sGC/cGMP/PKG pathway.AS received a scholarship from FCT (SFRH/BD/65112/2009).info:eu-repo/semantics/publishedVersio

The effects of cannabinoids on glioblastoma growth: A systematic review with meta-analysis of animal model studies

Glioblastoma multiforme (GBM) is the most frequent and aggressive malignant brain tumour, with a poor prognosis despite available surgical and radio-chemotherapy, rising the necessity for searching alternative therapies. Several preclinical studies evaluating the efficacy of cannabinoids in animal models of GBM have been described, but the diversity of experimental conditions and of outcomes hindered definitive conclusions about cannabinoids efficacy. A search in different databases (Pubmed, Web of Science, Scopus and SciELO) was conducted during June 2019 to systematically identify publications evaluating the effects of cannabinoids in murine xenografts models of GBM. The tumour volume and number of animals were extracted, and a random effects meta-analysis of these results was performed to estimate the efficacy of cannabinoids. The impact of different experimental factors and publication bias on the efficacy of cannabinoids was also assessed. Nine publications, which satisfied the inclusion criteria, were identified and subdivided in 22 studies involving 301 animals. Overall, cannabinoid therapy reduced the fold of increase in tumour volume in animal models of GBM, when compared with untreated controls. The overall weighted standardized difference in means (WSDM) for the effect of cannabinoids was -1.399 (95% CI: -1.900 to -0.898; P-value<0.0001). Furthermore, treatment efficacy was observed for different types of cannabinoids, alone or in combination, and for different treatment durations. Cannabinoid therapy was still effective after correcting for publication bias. The results indicate that cannabinoids reduce the tumour growth in animal models of GBM, even after accounting for publication bias.Operação Centro-01-0145-FEDER-000019-C4-Centro de Competências em Cloud Computinginfo:eu-repo/semantics/publishedVersio

The sex bias of cancer

In cancers of hormone-dependent organs like women breast and reproductive organs, endometrium and ovaries, and men’s prostate and testicular cancer, the roles of sex hormones and deregulation of hormone axes are well-documented. More strikingly, epidemiological data highlights significant differences between sexes in the incidence of various cancers in non-reproductive organs, where the role of sex hormones has been less studied. In an era when personalised medicine is gaining recognition, understanding molecular, cellular and biological differences between men and women is timely for developing more appropriate therapeutic interventions according to gender. In this review we show that sex hormones also shape much of the deregulated cellular and molecular pathways leading to cell proliferation and cancer in nonreproductive organs.info:eu-repo/semantics/acceptedVersio

Adenosine inhibits human astrocyte proliferation independently of adenosine receptor activation

Brain adenosine concentrations can reach micromolar concentrations in stressful situations such as stroke, neurodegenerative diseases or hypoxic regions of brain tumours. Adenosine can act by receptor-independent mechanism by reversing the reaction catalysed by S-adenosylhomocysteine (SAH) hydrolase, leading to SAH accumulation and inhibition of S-adenosylmethionine (SAM)-dependent methyltransferases. Astrocytes are essential in maintaining brain homeostasis but their pathological activation and uncontrolled proliferation plays a role in neurodegeneration and glioma. Adenosine can affect cell proliferation, but the effect of increased adenosine concentration on proliferation of astrocytes is not clarified and was addressed in present work. Human astrocytes (HA) were treated for 3 days with test drugs. Cell proliferation/viability was assessed by the MTT assay and by cell counting. Cell death was evaluated by assessing lactate dehydrogenase (LDH) release and by western blot analysis of αII-Spectrin cleavage. 30µM-Adenosine caused a 40%±3% (p < .05, n = 5) reduction in cell proliferation/viability, an effect reversed by 2U/ml-adenosine deaminase, but unchanged in the presence of antagonists of any of the adenosine receptors. Adenosine alone did not induce cell death. 100µM-Homocysteine alone caused 16%±3% (p < .05) decrease in HA proliferation. Combined action of adenosine and homocysteine decreased HA proliferation by 76%±4%, an effect higher (p < .05) than the sum of the effect of adenosine and homocysteine alone (56%±5%). The inhibitory effect of adenosine on HA proliferation/viability was mimicked by two adenosine kinase inhibitors and attenuated in the presence of folate (100µM) or SAM (50-100µM). The results suggest that adenosine reduces HA proliferation by a receptor-independent mechanism probably involving reversal of SAH hydrolase-catalysed reaction.info:eu-repo/semantics/acceptedVersio

Sensors in the Detection of Abused Substances in Forensic Contexts: A Comprehensive Review

orensic toxicology plays a pivotal role in elucidating the presence of drugs of abuse in both biological and solid samples, thereby aiding criminal investigations and public health initiatives. This review article explores the significance of sensor technologies in this field, focusing on diverse applications and their impact on the determination of drug abuse markers. This manuscript intends to review the transformative role of portable sensor technologies in detecting drugs of abuse in various samples. They offer precise, efficient, and real-time detection capabilities in both biological samples and solid substances. These sensors have become indispensable tools, with particular applications in various scenarios, including traffic stops, crime scenes, and workplace drug testing. The integration of portable sensor technologies in forensic toxicology is a remarkable advancement in the field. It has not only improved the speed and accuracy of drug abuse detection but has also extended the reach of forensic toxicology, making it more accessible and versatile. These advancements continue to shape forensic toxicology, ensuring swift, precise, and reliable results in criminal investigations and public health endeavours.info:eu-repo/semantics/publishedVersio

GABAergic role in the disruption of wild cleaner fish behaviour under high CO2

Funding Information: We acknowledge CRIOBE research station staff for the help provided throughout this study. We also acknowledge Frederik Zuberer for providing the cleaner fish photo. Portuguese national funds funded this study through FCT – Fundação para a Ciência e Tecnologia , I.P., within the projects PTDC/BIA-BMA/0080/2021 (ChangingMoods), PTDC/MAR-EST/5880/2014 (MUTUALCHANGE), the strategic project UID/MAR/04292/2020 (MARE), LA/P/0069/2020 (ARNET) and a PhD scholarship ( SFRH/BD/111153/2015 ). The Company of Biologists supported this study through a research grant to J.R.P. ( JEB 170212–2017 ). J.R.P. was supported by FCT through the CEEC program 2021.01030.CEECIND. Publisher Copyright: © 2022 The Author(s)Ocean acidification is considered to affect fish behaviour through the disruption of GABAergic neurotransmission in controlled laboratory conditions, but less is known of the GABAergic role on fish behavioural performance in the wild. Most coral reef fishes engage in complex cleaning interactions, where they benefit from ectoparasite removal and stress relief. Here, we tested whether potential ocean acidification impairment of wild cleaning interactions, between the cleaner fish Labroides dimidiatus and its clients, can be explained by the GABAAR model. We used, the GABAA receptor agonist (muscimol) and antagonist (gabazine) for the first time in the wild and tested their effects on cleaning behaviour in Moorea Island (French Polynesia) to address natural interactions and recovery capacity. After exposure to expected ocean acidification conditions, the proportion of time spent advertising cleaning services, a measure of motivation to interact, dropped significantly relative to controls. Furthermore, the GABAergic antagonist gabazine recovered most CO2-induced behavioural alterations to control levels, consistent with the GABAAR model of altered Cl− flux in ocean acidification-exposed fish. However, muscimol treatment only produced the same behavioural alterations found with CO2 exposure in time spent advertising cleaning. Our results support the evidence that ocean acidification alters some components of cleaning behaviour through GABAA receptor modulation with potential cascading effects on coral reef health and structure.publishe

Action of Curcumin on Glioblastoma Growth: A Systematic Review with Meta-Analysis of Animal Model Studies

Gliomas are aggressive brain tumors with poor prognosis even after surgical removal and radio-chemotherapy, stressing the urgency to find alternative therapies. Several preclinical studies evaluating the anticancer effect of curcumin in animal models of glioma are reported, but a systematic review with meta-analysis of these studies, considering the different experimental conditions used, has not been made up to this date. A search in different databases (Pubmed, Web of Science, Scopus, and SciELO) following the PRISMA statement was conducted during November 2023 to systematically identify articles assessing the effect of curcumin in murine xenograft models of glioma and identified 15 articles, which were subdivided into 24 studies. Tumor volume before and after treatment with curcumin or vehicle was extracted and the efficacy of curcumin was evaluated by performing a random effects meta-analysis of the data. Publication bias and the impact of different experimental conditions on curcumin efficacy were assessed. Treatment with curcumin decreased tumor volume. Comparing curcumin with control groups, the overall weighted standardized difference in means was −2.079 (95% CI: −2.816 to −1.341; p-value < 0.001). The curcumin effect was observed for different animal models, types of glioma cells, administration routes, and curcumin formulations. Publication bias was identified but does not invalidate curcumin’s effectiveness. The findings suggest the potential therapeutic efficacy of curcumin against glioma

The Combined Inhibitory Effect of the Adenosine A1 and Cannabinoid CB1 Receptors on cAMP Accumulation in the Hippocampus Is Additive and Independent of A1 Receptor Desensitization

Adenosine A1 and cannabinoid CB1 receptors are highly expressed in hippocampus where they trigger similar transduction pathways. We investigated how the combined acute activation of A1 and CB1 receptors modulates cAMP accumulation in rat hippocampal slices. The CB1 agonist WIN55212-2 (0.3–30 μM) decreased forskolin-stimulated cAMP accumulation with an EC50 of 6.6 ± 2.7 μM and an Emax⁡ of 31% ± 2%, whereas for the A1 agonist, N6-cyclopentyladenosine (CPA, 10–150 nM), an EC50 of 35 ± 19 nM, and an Emax⁡ of 29% ± 5 were obtained. The combined inhibitory effect of WIN55212-2 (30 μM) and CPA (100 nM) on cAMP accumulation was 41% ± 6% (n=4), which did not differ (P>0.7) from the sum of the individual effects of each agonist (43% ± 8%) but was different (P<0.05) from the effects of CPA or WIN55212-2 alone. Preincubation with CPA (100 nM) for 95 min caused desensitization of adenosine A1 activity, which did not modify the effect of WIN55212-2 (30 μM) on cAMP accumulation. In conclusion, the combined effect of CB1 and A1 receptors on cAMP formation is additive and CB1 receptor activity is not affected by short-term A1 receptor desensitization

Seawater carbonate chemistry and wild cleaner fish behaviour

Ocean acidification is considered to affect fish behaviour through the disruption of GABAergic neurotransmission in controlled laboratory conditions, but less is known of the GABAergic role on fish behavioural performance in the wild. Most coral reef fishes engage in complex cleaning interactions, where they benefit from ectoparasite removal and stress relief. Here, we tested whether potential ocean acidification impairment of wild cleaning interactions, between the cleaner fish Labroides dimidiatus and its clients, can be explained by the GABAAR model. We used, the GABAA receptor agonist (muscimol) and antagonist (gabazine) for the first time in the wild and tested their effects on cleaning behaviour in Moorea Island (French Polynesia) to address natural interactions and recovery capacity. After exposure to expected ocean acidification conditions, the proportion of time spent advertising cleaning services, a measure of motivation to interact, dropped significantly relative to controls. Furthermore, the GABAergic antagonist gabazine recovered most CO2-induced behavioural alterations to control levels, consistent with the GABAAR model of altered Cl− flux in ocean acidification-exposed fish. However, muscimol treatment only produced the same behavioural alterations found with CO2 exposure in time spent advertising cleaning. Our results support the evidence that ocean acidification alters some components of cleaning behaviour through GABAA receptor modulation with potential cascading effects on coral reef health and structure

Paleoenvironments and human adaptations during the Last Glacial Maximum in the Iberian Peninsula: A review

The Iberian Peninsula is considered one of the most well-suited regions in Europe to develop studies on the relationship between environmental changes and human adaptations across the Late Pleistocene. Due to its southwesternmost cul-de-sac position and eco-geographical diversity, Paleolithic Iberia was the stage of cyclical cultural/technological changes, linked to fluctuations in climate and environments, human demographics, and the size, extension, and type of social exchange networks. Such dynamics are particularly evident during the Last Glacial Maximum (LGM) timeframe, with a series of innovations emerging in the archaeological record, marking the transitions between the traditionally defined Gravettian, Proto-Solutrean, Solutrean, and Magdalenian technocomplexes. Stemming from a workshop organized in Erlangen in 2019 on 'The Last Glacial Maximum in Europe - state of knowledge in Geosciences and Archaeology', this paper presents, in the first part, an updated review on the paleoenvironments and human adaptations across four macro-regions (Northern, Inland, Mediterranean, and Western Atlantic Façade) in Iberia during the LGM; and, in a second part, a discussion on the pronounced interregional variability, unresolved research questions, and the most promising research topics for future studies