Publications by authors named "Luis M Botana"

223 Publications

Serotonin involvement in okadaic acid-induced diarrhoea in vivo.

Arch Toxicol 2021 Aug 20;95(8):2797-2813. Epub 2021 Jun 20.

Departamento de Farmacología, Facultad de Veterinaria, Universidade de Santiago de Compostela, 27002, Lugo, Spain.

The consumption of contaminated shellfish with okadaic acid (OA) group of toxins leads to diarrhoeic shellfish poisoning (DSP) characterized by a set of symptoms including nausea, vomiting and diarrhoea. These phycotoxins are Ser/Thr phosphatase inhibitors, which produce hyperphosphorylation in cellular proteins. However, this inhibition does not fully explain the symptomatology reported and other targets could be relevant to the toxicity. Previous studies have indicated a feasible involvement of the nervous system. We performed a set of in vivo approaches to elucidate whether neuropeptide Y (NPY), Peptide YY (PYY) or serotonin (5-HT) was implicated in the early OA-induced diarrhoea. Fasted Swiss female mice were administered NPY, PYY(3-36) or cyproheptadine intraperitoneal prior to oral OA treatment (250 µg/kg). A non-significant delay in diarrhoea onset was observed for NPY (107 µg/kg) and PYY(3-36) (1 mg/kg) pre-treatment. On the contrary, the serotonin antagonist cyproheptadine was able to block (10 mg/kg) or delay (0.1 and 1 mg/kg) diarrhoea onset suggesting a role of 5-HT. This is the first report of the possible involvement of serotonin in OA-induced poisoning.
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http://dx.doi.org/10.1007/s00204-021-03095-zDOI Listing
August 2021

Anhydroexfoliamycin, a Secondary Metabolite, Mitigates Microglia-Driven Inflammation.

ACS Chem Neurosci 2021 Jul 10;12(13):2336-2346. Epub 2021 Jun 10.

Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain.

Anhydroexfoliamycin, a secondary metabolite from , has shown antioxidant properties in primary cortical neurons reducing neurodegenerative hallmarks diseases, both and models. Activated microglia, in the central nervous system, plays a crucial role in neuroinflammation and is associated with neurodegeneration. Therefore, the aim of the present study was to determine the anti-inflammatory and antioxidant potential of the anhydroexfoliamycin over microglia BV2 cells. Neuroinflammation was simulated by incubation of microglia cells in the presence of lipopolysaccharide to activate proinflammatory transduction pathways. Moreover, a coculture of neuron SH-SY5Y and microglia BV2 cells was used to evaluate the neuroprotective properties of the metabolite. When microglia cells were preincubated with anhydroexfoliamycin, proinflammatory pathways, such as the translocation of the nuclear factor κB, the phosphorylation of c-Jun N-terminal kinase, and the inducible nitric oxide synthase expression, were inhibited. In addition, intracellular reactive oxygen species generation and the liberation of nitric oxide, interleukin 6, and tumor necrosis factor α were also decreased. Besides, the -derived compound showed antioxidant properties promoting the translocation of the factor erythroid 2-related factor 2 and protecting the SH-SY5Y cells from the neurotoxic mediators released by activated microglia. The effects of this compound were at the same level as the immunosuppressive drug cyclosporine A. Therefore, these results indicate that anhydroexfoliamycin is a promising tool to control microglia-driven inflammation with therapeutic potential in neuroinflammation.
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http://dx.doi.org/10.1021/acschemneuro.1c00033DOI Listing
July 2021

Single and combined effects of regulated and emerging mycotoxins on viability and mitochondrial function of SH-SY5Y cells.

Food Chem Toxicol 2021 Aug 29;154:112308. Epub 2021 May 29.

Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, 27002, Spain.

Co-occurrence of emerging and regulated mycotoxins in contaminated samples has been widely documented, but studies about their combined toxicity are scarce. In this report, the regulated mycotoxins deoxynivalenol, fumonisin B1 and zearalenone, and the emerging ones enniatin A, enniatin B and beauvericin were tested in SH-SY5Y human neuroblastoma cells. Their individual and binary combined effects on cell viability and mitochondrial function were evaluated. The results with individual mycotoxins revealed that deoxynivalenol and emerging mycotoxins were the most damaging to neuronal cells, presenting IC values between 0.35 and 2.4 μM. Interestingly, non-regulated mycotoxins triggered apoptosis by affecting to mitochondrial membrane potential. However, when regulated and non-regulated mycotoxins were binary mixed, antagonistic effects were found in all cases. Finally, cow feed and milk extracts were analysed by UHPLC-MS/MS, detecting the presence of several mycotoxins included in this study. These extracts were tested in neuroblastoma cells, and damaging effects on cell viability were found. Although binary combinations of mycotoxins produced antagonistic effects, their mixture in natural matrixes induces greater effects than expected. Therefore, it would be interesting to explore the matrix influence on mycotoxin toxicity, and to continue studying the neurotoxic mechanism of action of emerging mycotoxins, as they could be a health hazard.
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http://dx.doi.org/10.1016/j.fct.2021.112308DOI Listing
August 2021

Cyclophilins A, B, and C Role in Human T Lymphocytes Upon Inflammatory Conditions.

Front Immunol 2021 30;12:609196. Epub 2021 Mar 30.

Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain.

Cyclophilins (Cyps) are a group of peptidyl-prolyl isomerases that play crucial roles in regulatory mechanisms of cellular physiology and pathology in several inflammatory conditions. Their receptor, CD147, also participates in the development and progression of the inflammatory response. Nevertheless, the main function of Cyps and their receptor are yet to be deciphered. The release of CypA and the expression of the CD147 receptor in activated T lymphocytes were already described, however, no data are available about other Cyps in these cells. Therefore, in the present work intra and extracellular CypA, B and C levels were measured followed by induced inflammatory conditions. After activation of T lymphocytes by incubation with concanavalin A, both intra and extracellular Cyps levels and the CD147 membrane receptor expression were increased leading to cell migration towards circulating CypA and CypB as chemoattractants. When CypA was modulated by natural and synthetic compounds, the inflammatory cascade was avoided including T cell migration. Our results strengthen the relationship between CypA, B, and C, their receptor, and the inflammatory process in human T lymphocytes, associating CypC with these cells for the first time.
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http://dx.doi.org/10.3389/fimmu.2021.609196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042163PMC
July 2021

Multianalyte method for the determination of regulated, emerging and modified mycotoxins in milk: QuEChERS extraction followed by UHPLC-MS/MS analysis.

Food Chem 2021 Sep 23;356:129647. Epub 2021 Mar 23.

Departamento de Farmacología, Facultad de Veterinaria, Universidade de Santiago de Compostela, 27002 Lugo, Spain. Electronic address:

A simple method for the quantification of 40 mycotoxins in milk was developed. This method is based on a QuEChERS extraction followed by the ultra-high liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) detection, and allows the simultaneous analysis of regulated, emerging, and modified mycotoxins. A sample treatment procedure was optimized to include a concentration step for the analysis of some compounds such as aflatoxin M. The method was in-house validated in terms of limits of detection (LODs), limits of quantification (LOQs), linearity, recoveries, and precision. LOQs lower than 10 ng/mL were obtained, and recoveries ranged from 61% to 120% with a precision, expressed as the relative standard deviation, lower than 15%. Therefore, acceptable performance characteristics were obtained fulfilling European regulations. The method was successfully applied for the quantification of mycotoxins in raw milk. It can be highlighted high occurrence of beauvericin and enniatins were found in low amounts.
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http://dx.doi.org/10.1016/j.foodchem.2021.129647DOI Listing
September 2021

Cytotoxic Mechanism of Sphaerodactylomelol, an Uncommon Bromoditerpene Isolated from .

Molecules 2021 Mar 4;26(5). Epub 2021 Mar 4.

MARE-Marine and Environmental Sciences Centre, ESTM, Politécnico de Leiria, 2520-614 Peniche, Portugal.

Marine natural products have exhibited uncommon chemical structures with relevant antitumor properties highlighting their potential to inspire the development of new anticancer agents. The goal of this work was to study the antitumor activities of the brominated diterpene sphaerodactylomelol, a rare example of the dactylomelane family. Cytotoxicity (10-100 µM; 24 h) was evaluated on tumor cells (A549, CACO-2, HCT-15, MCF-7, NCI-H226, PC-3, SH-SY5Y, SK-ML-28) and the effects estimated by MTT assay. Hydrogen peroxide (HO) levels and apoptosis biomarkers (membrane translocation of phosphatidylserine, depolarization of mitochondrial membrane potential, Caspase-9 activity, and DNA condensation and/or fragmentation) were studied in the breast adenocarcinoma cellular model (MCF-7) and its genotoxicity on mouse fibroblasts (L929). Sphaerodactylomelol displayed an IC range between 33.04 and 89.41 µM without selective activity for a specific tumor tissue. The cells' viability decrease was accompanied by an increase on HO production, a depolarization of mitochondrial membrane potential and an increase of Caspase-9 activity and DNA fragmentation. However, the DNA damage studies in L929 non-malignant cell line suggested that this compound is not genotoxic for normal fibroblasts. Overall, the results suggest that the cytotoxicity of sphaerodactylomelol seems to be mediated by an increase of HO levels and downstream apoptosis.
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http://dx.doi.org/10.3390/molecules26051374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961984PMC
March 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Crosstalk between cyclophilins and T lymphocytes in coronary artery disease.

Exp Cell Res 2021 Mar 11;400(2):112514. Epub 2021 Feb 11.

Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, 27002, Spain; Grupo Investigación Biosdiscovery, IDIS, Spain.

Cardiovascular diseases and atherosclerosis are currently some of the most widespread diseases of our time. Within cardiovascular disease, coronary artery disease and underlying atherosclerosis were recently linked with systemic and local inflammation. Cyclophilins participate in the initiation and progression of these inflammatory-related diseases. Cyclophilins are released into the extracellular space upon inflammatory stimuli and participate in the pathology of cardiovascular diseases. The cell surface receptor for extracellular cyclophilins, the CD147 receptor, also contributes to coronary artery disease pathogenesis. Nevertheless, the physiological relevance of cyclophilin's family and their receptor in cardiovascular diseases remains unclear. The present study aimed to better understand the role of cyclophilins in cardiovascular artery disease and their relationship with inflammation. Hence, cyclophilins and pro-inflammatory interleukins were measured in the serum of 30 subjects (divided into three groups according to coronary artery disease status: 10 patients with acute coronary syndrome, 10 patients with chronic coronary artery disease, and 10 control volunteers). In addition, cyclophilin levels and CD147 receptor expression were measured in T lymphocytes purified from these subjects. Cyclophilin A, B, and C, pro-inflammatory interleukins, and CD147 membrane expression were significantly elevated in patients with coronary artery disease.
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http://dx.doi.org/10.1016/j.yexcr.2021.112514DOI Listing
March 2021

Targeting Chloride Ion Channels: New Insights into the Mechanism of Action of the Marine Toxin Azaspiracid.

Chem Res Toxicol 2021 Mar 29;34(3):865-879. Epub 2021 Jan 29.

Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, Facultad de Veterinaria, Universidad de Santiago de Compostela, Campus Universitario s/n, 27002 Lugo, España.

Azaspiracids (AZAs) are marine toxins produced by dinoflagellates belonging to the genera and that caused human intoxications after consumption of contaminated fishery products, such as mussels. However, the exact mechanism for the AZA induced cytotoxic and neurotoxic effects is still unknown. In this study several pharmacological approaches were employed to evaluate the role of anion channels on the AZA effects that demonstrated that cellular anion dysregulation was involved in the toxic effects of these compounds. The results presented here demonstrated that volume regulated anion channels (VRACs) are affected by this group of toxins, and, because there is not any specific activator of VRACs besides the intracellular application of GTPγ-S molecule, this group of natural compounds could represent a powerful tool to analyze the role of these channels in cellular homeostasis. In addition to this, in this work, a detailed pharmacological approach was performed in order to elucidate the anion channels present in human HEK293 cells as well as their regulation by the marine toxins azaspiracids. Altogether, the data presented here demonstrated that the effect of azaspiracids in human cells was completely dependent on ATP-regulated anion channels, whose upregulation by these toxins could lead to regulatory volume decrease and underlie the reported toxicity of these compounds.
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http://dx.doi.org/10.1021/acs.chemrestox.0c00494DOI Listing
March 2021

DSP Toxin Distribution across Organs in Mice after Acute Oral Administration.

Mar Drugs 2021 Jan 8;19(1). Epub 2021 Jan 8.

Departamento de Farmacologia, Facultad de Veterinaria, Universidad de Santiago de Compostela, Campus Universitario, 27002 Lugo, Spain.

Okadaic acid (OA) and its main structural analogs dinophysistoxin-1 (DTX1) and dinophysistoxin-2 (DTX2) are marine lipophilic phycotoxins distributed worldwide that can be accumulated by edible shellfish and can cause diarrheic shellfish poisoning (DSP). In order to study their toxicokinetics, mice were treated with different doses of OA, DTX1, or DTX2 and signs of toxicity were recorded up to 24 h. Toxin distribution in the main organs from the gastrointestinal tract was assessed by liquid chromatography-mass spectrometry (LC/MS/MS) analysis. Our results indicate a dose-dependency in gastrointestinal absorption of these toxins. Twenty-four hours post-administration, the highest concentration of toxin was detected in the stomach and, in descending order, in the large intestine, small intestine, and liver. There was also a different toxicokinetic pathway between OA, DTX1, and DTX2. When the same toxin doses are compared, more OA than DTX1 is detected in the small intestine. OA and DTX1 showed similar concentrations in the stomach, liver, and large intestine tissues, but the amount of DTX2 is much lower in all these organs, providing information on DSP toxicokinetics for human safety assessment.
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http://dx.doi.org/10.3390/md19010023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826939PMC
January 2021

Tavarua Deoxyriboside A and Jasplakinolide as Potential Neuroprotective Agents: Effects on Cellular Models of Oxidative Stress and Neuroinflammation.

ACS Chem Neurosci 2021 01 22;12(1):150-162. Epub 2020 Dec 22.

Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo 27002, Spain.

The oceans harbor a great reservoir of molecules with unknown bioactivities, which could be useful for the treatment of illnesses that nowadays have no cure, such as neurodegenerative diseases. In this work, we evaluated the neuroprotective potential of the marine Fijian compounds tavarua deoxyriboside A and jasplakinolide against oxidative stress and neuroinflammation, crucial mechanisms in neurodegeneration. Both metabolites protected SH-SY5Y human neuroblastoma cells from HO damage, improving mitochondrial function and activating the antioxidant systems of cells. These effects were mediated by their ability of inducing Nrf2 translocation. In BV2 microglial cells activated with lipopolysaccharide, Fijian metabolites also displayed promising results, decreasing the release of proinflammatory mediators (ROS, NO, cytokines) through the reduction of gp91 and NFkB-p65 expression. Finally, we performed a coculture among both cell lines, in which treatment with compounds protected SH-SY5Y cells from activated microglia, corroborating their neuroprotective effects. These results suggest that tavarua deoxyriboside A and jasplakinolide could be used as candidate molecules for further studies against neurodegeneration.
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http://dx.doi.org/10.1021/acschemneuro.0c00626DOI Listing
January 2021

Lipophilic toxins occurrence in non-traditional invertebrate vectors from North Atlantic Waters (Azores, Madeira, and Morocco): Update on geographical tendencies and new challenges for monitoring routines.

Mar Pollut Bull 2020 Dec 17;161(Pt B):111725. Epub 2020 Oct 17.

Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, Porto 4619-007, Portugal; Interdisciplinary Center of Marine and Environmental Research-CIMAR/CIIMAR, University of Porto, Novo Edifício do Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, 4450-208 S/N Matosinhos, Portugal. Electronic address:

In the last decades, due to monitoring programs and strict legislation poisoning incidents occurrence provoked by ingestion of naturally contaminated marine organisms has decreased. However, climate change and anthropogenic interference contributed to the expansion and establishment of toxic alien species to more temperate ecosystems. In this work, the coasts of Madeira, São Miguel islands and the northwestern Moroccan coast were surveyed for four groups of lipophilic toxins (yessotoxins, azaspiracids, pectenotoxins, and spirolides), searching for new vectors and geographical tendencies. Twenty-four species benthic organisms were screened using UHPLC-MS/MS technique. We report 19 new vectors for these toxins, six of them with commercial interest (P. aspera, P. ordinaria, C. lampas, P. pollicipes, H. tuberculata and P. lividus). Regarding toxin uptake a south-north gradient was detected. This study contributes to the update of monitoring routines and legislation policies, comprising a wider range of vectors, to better serve consumers and ecosystems preservation.
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http://dx.doi.org/10.1016/j.marpolbul.2020.111725DOI Listing
December 2020

Detection of Cyclic Imine Toxins in Dietary Supplements of Green Lipped Mussels () and in Shellfish .

Toxins (Basel) 2020 09 24;12(10). Epub 2020 Sep 24.

Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain.

Seafood represents a significant part of the human staple diet. In the recent years, the identification of emerging lipophilic marine toxins has increased, leading to the potential for consumers to be intoxicated by these toxins. In the present work, we investigate the presence of lipophilic marine toxins (both regulated and emerging) in commercial seafood products from non-European locations, including mussels from Chile, clams and from the Southeast Pacific and Vietnam, and food supplements based on mussels formulations of from New Zealand. All these products were purchased from European Union markets and they were analyzed by UPLC-MS/MS. Results showed the presence of the emerging pinnatoxin-G in mussels at levels up to 5.2 µg/kg and azaspiracid-2 and pectenotoxin-2 in clams up to 4.33 µg/kg and 10.88 µg/kg, respectively. This study confirms the presence of pinnatoxins in Chile, one of the major mussel producers worldwide. Chromatograms showed the presence of 13-desmethyl spirolide C in dietary supplements in the range of 33.2-97.9 µg/kg after an extraction with water and methanol from 0.39 g of the green lipped mussels powder. As far as we know, this constitutes the first time that an emerging cyclic imine toxin in dietary supplements is reported. Identifying new matrix, locations, and understanding emerging toxin distribution area are important for preventing the risks of spreading and contamination linked to these compounds.
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http://dx.doi.org/10.3390/toxins12100613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601114PMC
September 2020

Partial Blockade of Human Voltage-Dependent Sodium Channels by the Marine Toxins Azaspiracids.

Chem Res Toxicol 2020 10 16;33(10):2593-2604. Epub 2020 Sep 16.

Departamento de Farmacologı́a, Farmacia y Tecnologı́a Farmacéutica, Facultade de Veterinaria, Universidade de Santiago de Compostela, Campus Universitario s/n, 27002 Lugo, Spain.

Azaspiracid toxins were first identified at the end of the last century in Irish mussels, and during the last two decades considerable cytotoxic and neurotoxic effects caused by these toxins have been described. Azaspiracids are synthesized by dinoflagellates and accumulate in several species of filter-feeding bivalve mollusks, thereby incorporating into the food chain and causing human intoxications. Among the cellular effects of azaspiracids, inhibition of spikes in neurons and hyperpolarization of the neuronal membrane potential have been reported; however, the underlying processes leading to these effects were never elucidated. In this regard, initial studies reported no activity of the toxin in neuronal voltage-gated sodium channels, and a recent work described no effect of azaspiracid-1 on the inactivation kinetics of voltage-gated sodium channels; however, the relationship between the known alterations of the cytoskeleton caused by these toxins and their effects on ion channels has never been evaluated. In this work, the cytotoxic effect of azaspiracids was evaluated in human cells as well as their activity on voltage-gated sodium channels and in cell morphology in order to unravel the cellular targets involved in the mechanism of action of this group of marine toxins. The data reported here demonstrate, for the first time, that both azaspiracid-1 and azaspiracid-2 caused a rapid concentration-dependent inhibition of the amplitude of voltage-gated sodium currents without affecting their inactivation kinetics, an effect that was increased after long-term treatment of the cells with the toxin. Simultaneously, long-term exposure of the cells to azaspiracids caused a profound alteration of the cell cytoskeleton and decreased the metabolic activity of human cells. Altogether, the data presented here indicate that the partial blockade of voltage-gated sodium channels by these toxins is not related with their effect on the actin cytoskeleton. However, since azaspiracids are common toxins in European waters, their effect on voltage-gated sodium channels, first reported here, should be considered to avoid synergistic toxicity with other marine toxins that are known potent blockers of sodium channels such as the saxitoxins and tetrodotoxins, but further studies are needed in order to elucidate how these compounds alter ion homeostasis.
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http://dx.doi.org/10.1021/acs.chemrestox.0c00216DOI Listing
October 2020

In Vivo Evaluation of the Chronic Oral Toxicity of the Marine Toxin Palytoxin.

Toxins (Basel) 2020 07 30;12(8). Epub 2020 Jul 30.

Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica, Facultade de Veterinaria, Universidade de Santiago de Compostela, Campus Universitario s/n, 27002 Lugo, Spain.

(PLTX) is one of the most poisonous substances known to date and considered as an emergent toxin in Europe. Palytoxin binds to the Na-K ATPase, converting the enzyme in a permeant cation channel. This toxin is known for causing human fatal intoxications associated with the consumption of contaminated fish and crustaceans such as crabs, groupers, mackerel, and parrotfish. Human intoxications by PLTX after consumption of contaminated fishery products are a serious health issue and can be fatal. Different reports have previously explored the acute oral toxicity of PLTX in mice. Although the presence of palytoxin in marine products is currently not regulated in Europe, the European Food Safety Authority expressed its opinion on PLTX and demanded assessment for chronic toxicity studies of this potent marine toxin. In this study, the chronic toxicity of palytoxin was evaluated after oral administration to mice by gavage during a 28-day period. After chronic exposure of mice to the toxin, a lethal dose 50 (LD) of 0.44 µg/kg of PLTX and a No-Observed-Adverse-Effect Level (NOAEL) of 0.03 µg/kg for repeated daily oral administration of PLTX were determined. These results indicate a much higher chronic toxicity of PLTX and a lower NOAEL than that previously described in shorter treatment periods, pointing out the need to further reevaluate the levels of this compound in marine products.
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http://dx.doi.org/10.3390/toxins12080489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472043PMC
July 2020

Biological Activities of Cyclic and Acyclic B-Type Laxaphycins in SH-SY5Y Human Neuroblastoma Cells.

Mar Drugs 2020 Jul 15;18(7). Epub 2020 Jul 15.

Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27003 Lugo, Spain.

Laxaphycins are a family of non-ribosomal lipopeptides that have been isolated from several cyanobacteria. Some of these compounds have presented cytotoxic activities, but their mechanism of action is poorly understood. In this work, the already described laxaphycins B and B3, and acyclolaxaphycins B and B3 were isolated from the marine cyanobacteria . Moreover, two new acyclic compounds, [des-(Ala-Hle)] acyclolaxaphycins B and B3, were purified from the herviborous gastropod , with this being the first description of biotransformed laxaphycins. The structure of these new compounds was elucidated, together with the absolute configuration of acyclolaxaphycins B and B3. The bioactivities of the six peptides were determined in SH-SY5Y human neuroblastoma cells. Laxaphycins B and B3 were cytotoxic (IC: 1.8 and 0.8 µM, respectively) through the induction of apoptosis. In comparison, acyclic laxaphycins did not show cytotoxicity but affected mitochondrial functioning, so their effect on autophagy-related protein expression was analyzed, finding that acyclic peptides affected this process by increasing AMPK phosphorylation and inhibiting mTOR. This work confirms the pro-apoptotic properties of cyclic laxaphycins B and is the first report indicating the effects on autophagy of their acyclic analogs. Moreover, gastropod-derived compounds presented ring opening and amino-acids deletion, a biotransformation that had not been previously described.
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http://dx.doi.org/10.3390/md18070364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404270PMC
July 2020

Futunamine, a Pyrrole-Imidazole Alkaloid from the Sponge aff. Collected off the Futuna Islands.

J Nat Prod 2020 07 6;83(7):2299-2304. Epub 2020 Jul 6.

Marine Biodiscovery, School of Chemistry and Ryan Institute, National University of Ireland Galway (NUI Galway), University Road, H91 TK33 Galway, Ireland.

The chemical investigation of the sponge aff. collected around Futuna Islands in the Pacific Ocean led to the isolation of three new dimeric pyrrole 2-aminoimidazole alkaloids (PIAs). Futunamine () features an unprecedented pyrrolo[1,2-]imidazole core, while two other new dimeric PIAs were identified as analogues of palau'amine. Together with other known PIAs isolated from this species, they were shown to exhibit anti-inflammatory and neuroprotective activities.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00223DOI Listing
July 2020

Sphaerococcus coronopifolius bromoterpenes as potential cancer stem cell-targeting agents.

Biomed Pharmacother 2020 Aug 30;128:110275. Epub 2020 May 30.

MARE-Marine and Environmental Sciences Centre, Instituto Politécnico de Leiria, 2520-630 Peniche, Portugal. Electronic address:

Cancer is one of the major threats to human health and, due to distinct factors, it is expected that its incidence will increase in the next decades leading to an urgent need of new anticancer drugs development. Ongoing experimental and clinical observations propose that cancer cells with stem-like properties (CSCs) are involved on the development of lung cancer chemoresistance. As tumour growth and metastasis can be controlled by tumour-associated stromal cells, the main goal of this study was to access the antitumor potential of five bromoterpenes isolated from Sphaerococcus coronopifolius red alga to target CSCs originated in a co-culture system of fibroblast and lung malignant cells. Cytotoxicity of compounds (10-500 μM; 72 h) was evaluated on monocultures of several malignant and non-malignant cells lines (HBF, BEAS-2B, RenG2, SC-DRenG2) and the effects estimated by MTT assay. Co-cultures of non-malignant human bronchial fibroblasts (HBF) and malignant human bronchial epithelial cells (RenG2) were implemented and the compounds ability to selectively kill CSCs was evaluated by sphere forming assay. The interleucine-6 (IL-6) levels were also determined as cytokine is crucial for CSCs. Regarding the monocultures results bromosphaerol selectively eliminated the malignant cells. Both 12S-hydroxy-bromosphaerol and 12R-hydroxy-bromosphaerol steroisomers were cytotoxic towards non-malignant bronchial BEAS-2B cell line, IC of 4.29 and 4.30 μM respectively. However, none of the steroisomers induced damage in the HBFs. As to the co-cultures, 12R-hydroxy-bromosphaerol revealed the highest cytotoxicity and ability to abrogate the malignant stem cells; however its effects were IL-6 independent. The results presented here are the first evidence of the potential of these bromoterpenes to abrogate CSCs opening new research opportunities. The 12R-hydroxy-bromosphaerol revealed to be the most promising compound to be test in more complex living models.
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http://dx.doi.org/10.1016/j.biopha.2020.110275DOI Listing
August 2020

Magnetic nanostructures for marine and freshwater toxins removal.

Chemosphere 2020 Oct 10;256:127019. Epub 2020 May 10.

Departamento de Farmacología, Facultad de Veterinaria, Universidade de Santiago de Compostela, 27002, Lugo, Spain. Electronic address:

Marine and freshwater toxins contaminate water resources, shellfish and aquaculture products, causing a broad range of toxic effects in humans and animals. Different core-shell nanoparticles were tested as a new sorbent for removing marine and freshwater toxins from liquid media. Water solutions were contaminated with 20 μg/L of marine toxins and up to 50 μg/L of freshwater toxins and subsequently treated with 250 or 125 mg/L of nanoparticles. Under these conditions, carbon nanoparticles removed around 70% of saxitoxins, spirolides, and azaspiracids, and up to 38% of diarrheic shellfish poisoning toxins. In the case of freshwater toxins, the 85% of microcystin LR was eliminated; other cyclic peptide toxins were also removed in a high percentage. Marine toxins were adsorbed in the first 5 min of contact, while for freshwater toxins it was necessary 60 min to reach the maximum adsorption. Toxins were recovered by extraction from nanoparticles with different solvents. Gymnodinium catenatum, Prorocentrum lima, and Microcystis aeruginosa cultures were employed to test the ability of nanoparticles to adsorb toxins in a real environment, and the same efficacy to remove toxins was observed in these conditions. These results suggest the possibility of using the nanotechnology in the treatment of contaminated water or in chemical analysis applications.
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http://dx.doi.org/10.1016/j.chemosphere.2020.127019DOI Listing
October 2020

Oral Chronic Toxicity of the Safe Tetrodotoxin Dose Proposed by the European Food Safety Authority and Its Additive Effect with Saxitoxin.

Toxins (Basel) 2020 05 9;12(5). Epub 2020 May 9.

Laboratorio de Farmacología, Farmacia e Tecnoloxía Farmacéutica, Universidade de Santiago de Compostela, Facultad de Veterinaria, Campus Universitario s/n, 27002 Lugo, Spain.

Tetrodotoxin (TTX) is a potent natural toxin causative of human food intoxications that shares its mechanism of action with the paralytic shellfish toxin saxitoxin (STX). Both toxins act as potent blockers of voltage-gated sodium channels. Although human intoxications by TTX were initially described in Japan, nowadays increasing concern about the regulation of this toxin in Europe has emerged due to its detection in fish and mollusks captured in European waters. Currently, TTX is only regularly monitored in Dutch fishery products. However, the European Food Safety Authority (EFSA) has established a safety level of 44 µg/kg TTX as the amount of toxin that did not cause adverse effects in humans. This level was extrapolated considering initial data on its acute oral toxicity and EFSA remarked the need for chronic toxicity studies to further reduce the uncertainty of future toxin regulations. Thus, in this work, we evaluated the oral chronic toxicity of TTX using the safety levels initially recommended by EFSA in order to exclude potential human health risks associated with the worldwide expanding presence of TTX. Using internationally recommended guidelines for the assessment of oral chronic toxicity, the data provided here support the proposed safety level for TTX as low enough to prevent human adverse effects of TTX even after chronic daily exposure to the toxin. However, the combination of TTX with STX at doses above the maximal exposure level of 5.3 µg/kg body weight derived by EFSA increased the lethality of TTX, thus confirming that both TTX and paralytic shellfish toxins should be taken into account to assess human health risks.
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http://dx.doi.org/10.3390/toxins12050312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291010PMC
May 2020

Reevaluation of the acute toxicity of palytoxin in mice: Determination of lethal dose 50 (LD) and No-observed-adverse-effect level (NOAEL).

Toxicon 2020 Apr 24;177:16-24. Epub 2020 Jan 24.

Departamento de Farmacoloxía, Farmacia e Tecnología Farmacéutica, Facultade de Veterinaria, Universidade de Santiago de Compostela, Lugo, 27002, Spain. Electronic address:

Palytoxin is an emergent toxin in Europe and one of the most toxic substances know to date. The toxin disrupts the physiological functioning of the Na/K-ATPase converting the enzyme in a permeant cation channel. Human intoxications by PLTX after consumption of contaminated fishery products are a serious health issue and can be fatal. Several reports have previously investigated the oral and intraperitoneal toxicity of PLTX in mice. However, in all cases short observation periods (24 and 48 h) after toxin administration were evaluated. In this work, single oral or intraperitoneal doses of PLTX were administered to healthy mice and surviving animals were followed up for 96 h. The data obtained here allowed us to calculate the oral and intraperitoneal lethal doses 50 (LD) which were in the range of the values previously described. Surprisingly, the oral NOAEL for PLTX was more than 10 times lower than that previously described, a fact that indicates the need for the reevaluation of the levels of the toxin in edible fishery products.
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http://dx.doi.org/10.1016/j.toxicon.2020.01.010DOI Listing
April 2020

Neuroprotective Effects of Apple-Derived Drinks in a Mice Model of Inflammation.

Mol Nutr Food Res 2020 01 23;64(2):e1901017. Epub 2019 Dec 23.

Departamento de Farmacología, Facultad, de Veterinaria, Universidad de Santiago de Compostela, Lugo, 27003, Spain.

Scope: Fruit-derived drinks consumption is considered beneficial due to the antioxidant and neuroprotective effects of polyphenols separately, but studies including their total constituents are scarce. In this work, the antioxidant and anti-inflammatory neuroprotective effects of apple-derived beverages are determined in a mouse model of lipopolysaccharide (LPS)-induced inflammation.

Methods And Results: Preliminary antioxidant and neuroinflammatory experiments are carried out with 15 drink polyphenolic extracts in SH-SY5Y and BV2 cells, using H O as pro-oxidant and LPS as pro-inflammatory stimulus, respectively. Extracts improve antioxidant systems functioning and present neuroprotective mitochondrial-related effects. In microglia, extracts reduce reactive oxygen species and modulate cytokine release. To better mimic human consumption, four concentrated dealcoholized apple-derived drinks (three ciders and apple juice) are supplied to mice for 7 days in substitution of drinking water. Mice treated with beverages present reduced brain oxidative stress and inflammatory markers after LPS injection. Interestingly, genetic expression of antioxidant enzymes and glutathione levels are also greatly augmented after drink intake.

Conclusion: The results confirm the antioxidant and anti-inflammatory-mediated neuroprotective properties of apple-derived drinks, suggesting that their consumption could be a good approach for prevention of neurodegenerative disorders. To the authors' knowledge, this is the first description of cider neuroprotective effects.
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http://dx.doi.org/10.1002/mnfr.201901017DOI Listing
January 2020

Salen‑manganese complexes for controlling ROS damage: Neuroprotective effects, antioxidant activity and kinetic studies.

J Inorg Biochem 2020 02 14;203:110918. Epub 2019 Nov 14.

Departamento de Química Inorgánica, Facultade de Ciencias, Campus Terra, Universidade de Santiago de Compostela, Lugo, Spain. Electronic address:

A new manganese(III) complex [MnL(DCA)(HO)](HO)1 [HL is the chelating ligand N,N'-bis(2-hydroxy-3-methoxybenzylidene)-1,2-diaminopropane, and DCA is dicyanamide], has been prepared and characterized by different analytical and spectroscopic techniques. The tetragonally elongated octahedral geometry for the manganese coordination sphere was revealed by X-ray diffraction studies for 1. The antioxidant behavior of this complex and other manganese(III)-salen type complexes was tested through superoxide dismutase and catalase probes, and through the study of their neuroprotective effects in SH-SY5Y neuroblastoma cells. In this human neuronal model, these model complexes were found to improve cell survival in an oxidative stress model. During studies aimed to getting a better understanding of the kinetics of the processes involved in this antioxidant behavior, an important effect on the solvent in the kinetics of reaction of the complexes with HO was revealed that suggests a change in the mechanism of reaction of the complexes. The kinetic data in methanol and buffered aqueous solutions correlate well with the results of the test of catalase activity, thus showing that the rate determining step in the catalytic cycle corresponds to the initial reaction of the complexes with HO.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110918DOI Listing
February 2020

Gracilin-Derivatives as Lead Compounds for Anti-inflammatory Effects.

Cell Mol Neurobiol 2020 May 15;40(4):603-615. Epub 2019 Nov 15.

Pharmacology Department, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002, Lugo, Spain.

Gracilins are diterpenes derivative, isolated from the marine sponge Spongionella gracilis. Natural gracilins and synthetic derivatives have shown antioxidant, immunosuppressive, and neuroprotective capacities related to the affinity for cyclophilins. The aim of this work was to study anti-inflammatory and immunosuppressive pathways modulated by gracilin L and two synthetic analogues, compound 1 and 2, on a cellular model of inflammation. In this way, the murine BV2 microglia cell line was used. To carry out the experiments, microglia cells were pre-treated with compounds for 1 h and then stimulated with lipopolysaccharide for 24 h to determine reactive oxygen species production, mitochondrial membrane potential, the release of nitric oxide, interleukin-6 and tumor necrosis factor-α and the expression of Nuclear factor-erythroid 2-related factor 2, Nuclear Factor-κB, the inducible nitric oxide synthase, and the cyclophilin A. Finally, a co-culture of neuron SH-SY5Y and microglia BV2 cells was used to check the neuroprotective effect of these compounds. Cyclosporine A was used as a control of effect. The compounds were able to decrease inflammatory mediators, the expression of inflammatory target proteins as well as they activated anti-oxidative mechanism upon inflammatory conditions. For this reason, natural and synthetic gracilins could be interesting for developing anti-inflammatory drugs.
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http://dx.doi.org/10.1007/s10571-019-00758-5DOI Listing
May 2020

Gracilin A Derivatives Target Early Events in Alzheimer's Disease: in Vitro Effects on Neuroinflammation and Oxidative Stress.

ACS Chem Neurosci 2019 09 23;10(9):4102-4111. Epub 2019 Aug 23.

Departamento de Farmacología, Facultad de Veterinaria , Universidad de Santiago de Compostela , Lugo 27003 , Spain.

The search for compounds capable of targeting early pathological changes of Alzheimer̀s disease (AD), such as oxidative stress and neuroinflammation, is an important challenge. Gracilin A derivatives were recently synthesized, using a pharmacophore-directed retrosynthesis (PDR) strategy, and found to possess potent neuroprotective effects. In this work, the previously described derivatives - which demonstrated mitochondrial-mediated, antioxidant effects were chosen for further study. The ability of compounds to modulate the expression of antioxidant genes (, , , and ) was determined in SH-SY5Y cells, and the simplified derivatives and were found to be the most effective. The anti-neuroinflammatory properties of all derivatives were assessed in BV2 microglial cells activated with lipopolysaccharide (LPS). Several derivatives decreased the release of cytokines (Il-1β, IL-6, GM-CSF, and TNF-α) and other damaging molecules (ROS, NO) and also regulated the translocation of Nrf2 and NFκB, and reduced p38 activation. These protective effects were confirmed in a trans-well coculture with BV2 and SH-SY5Y cells and several derivatives increased SH-SY5Y survival. This present work demonstrates the neuroprotective properties of gracilin A derivatives, making them promising candidate drugs for AD. Particularly, derivatives and showed the greatest potential as lead compounds for further development.
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http://dx.doi.org/10.1021/acschemneuro.9b00329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654966PMC
September 2019

High Serum Cyclophilin C levels as a risk factor marker for Coronary Artery Disease.

Sci Rep 2019 07 22;9(1):10576. Epub 2019 Jul 22.

Pharmacology Department, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002, Lugo, Spain.

Cyclophilins (Cyps) are ubiquitous proteins that belong to the immunophilins family consistently associated with inflammatory and cardiovascular diseases. While levels of CypA have been extensively studied, less data are available for other Cyps. The purpose of this case-control study was to determine the relationship of Cyps (A, B, C and D) with coronary artery disease (CAD) and eight inflammation markers. Serum levels of Cyps, interleukins and metalloproteinases were measured in serum collected from 84 subjects. Participants were divided into two sub-groups based on CAD diagnosis: 40 CAD patients and 44 control volunteers. Serum levels of CypA, CypB and CypC, IL-1β and IL-6 were significantly higher in CAD patients. Bivariate correlation analysis revealed a significant positive correlation between Cyps and several blood and biochemical parameters. When the ability of Cyps levels for CAD diagnosis was evaluated, higher sensitivity and selectivity values were obtained with CypC (c-statistic 0.891, p < 0.001) indicating that it is a good marker of CAD disease, while less conclusive results were obtained with CypA (c-statistic 0.748, p < 0.001) and CypB (c-statistic 0.655, p < 0.014). In addition, significant correlations of traditional CAD risk factors and CypC were observed. In summary, high levels of CypC are a risk factor for CAD and therefore it can be proposed as a new biomarker for this disease.
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http://dx.doi.org/10.1038/s41598-019-46988-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646393PMC
July 2019

LC-MS/MS Analysis of the Emerging Toxin Pinnatoxin-G and High Levels of Esterified OA Group Toxins in Galician Commercial Mussels.

Toxins (Basel) 2019 07 5;11(7). Epub 2019 Jul 5.

Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain.

The occurrence of marine harmful algae is increasing worldwide and, therefore, the accumulation of lipophilic marine toxins from harmful phytoplankton represents a food safety threat in the shellfish industry. Galicia, which is a commercially important EU producer of edible bivalve mollusk have been subjected to recurring cases of mussel farm closures, in the last decades. This work aimed to study the toxic profile of commercial mussels () in order to establish a potential risk when ingested. For this, a total of 41 samples of mussels farmed in 3 Rías (Ares-Sada, Arousa, and Pontevedra) and purchased in 5 local markets were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Chromatograms showed the presence of okadaic acid (OA), dinophysistoxin-2 (DTX-2), pectenotoxin-2 (PTX-2), azaspiracid-2 (AZA-2), and the emerging toxins 13-desmethyl spirolide C (SPX-13), and pinnatoxin-G (PnTX-G). Quantification of each toxin was determined using their own standard calibration in the range 0.1%-50 ng/mL (R2 > 0.99) and by considering the toxin recovery (62-110%) and the matrix correction (33-211%). Data showed that OA and DTX-2 (especially in the form of esters) are the main risk in Galician mollusks, which was detected in 38 samples (93%) and 3 of them exceeded the legal limit (160 µg/kg), followed by SPX-13 that was detected in 19 samples (46%) in quantities of up to 28.9 µg/kg. Analysis from PTX-2, AZA-2, and PnTX-G showed smaller amounts. Fifteen samples (37%) were positive for PTX-2 (0.7-2.9 µg/kg), 12 samples (29%) for AZA-2 (0.1-1.8 µg/kg), and PnTX-G was detected in 5 mussel samples (12%) (0.4 µg/kg-0.9 µg/kg). This is the first time Galician mollusk was contaminated with PnTX-G. Despite results indicating that this toxin was not a potential risk through the mussel ingestion, it should be considered in the shellfish safety monitoring programs through the LC-MS/MS methods.
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http://dx.doi.org/10.3390/toxins11070394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669594PMC
July 2019

Gambierol Potently Increases Evoked Quantal Transmitter Release and Reverses Pre- and Post-Synaptic Blockade at Vertebrate Neuromuscular Junctions.

Neuroscience 2020 07 28;439:106-116. Epub 2019 Jun 28.

CEA, Institut des sciences du vivant Frédéric Joliot, Service d'Ingénierie Moléculaire des Protéines, Université Paris-Saclay, bâtiment 152, 91191 Gif sur Yvette, France; Institut des Neurosciences Paris-Saclay, UMR 9197 CNRS / Université Paris-Sud, CNRS, Gif sur Yvette, France.

Gambierol is a marine polycyclic ether toxin, first isolated from cultured Gambierdiscus toxicus dinoflagellates collected in French Polynesia. The chemical synthesis of gambierol permitted the analyses of its mode of action which includes the selective inhibition of voltage-gated K (K) channels. In the present study we investigated the action of synthetic gambierol at vertebrate neuromuscular junctions using conventional techniques. Gambierol was studied on neuromuscular junctions in which muscle nicotinic ACh receptors have been blocked with d-tubocurarine (postsynaptic block), or in junctions in which quantal ACh release has been greatly reduced by a low Ca-high Mg medium or by botulinum neurotoxin type-A (BoNT/A) (presynaptic block). Results show that nanomolar concentrations of gambierol inhibited the fast K current and prolonged the duration of the presynaptic action potential in motor nerve terminals, as revealed by presynaptic focal current recordings, increased stimulus-evoked quantal content in junctions blocked by high Mg-low Ca medium, and by BoNT/A, reversed the postsynaptic block produced by d-tubocurarine and increased the transient Ca signals in response to nerve-stimulation (1-10 Hz) in nerve terminals loaded with fluo-3/AM. The results suggest that gambierol, which on equimolar basis is more potent than 3,4-diaminopyridine, can have potential application in pathologies in which it is necessary to antagonize pre- or post-synaptic neuromuscular block, or both. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
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http://dx.doi.org/10.1016/j.neuroscience.2019.06.024DOI Listing
July 2020

Bromotryptamine and Bromotyramine Derivatives from the Tropical Southwestern Pacific Sponge .

Mar Drugs 2019 May 30;17(6). Epub 2019 May 30.

Marine Biodiscovery, School of Chemistry and Ryan Institute, National University of Ireland Galway (NUI Galway), University Road, H91 TK33 Galway, Ireland.

So far, the Futuna Islands located in the Central Indo-Pacific Ocean have not been inventoried for their diversity in marine sponges and associated chemical diversity. As part of the Tara Pacific expedition, the first chemical investigation of the sponge collected around the Futuna Islands yielded 18 brominated alkaloids: seven new bromotryptamine derivatives - and one new bromotyramine derivative together with 10 known metabolites of both families -. Their structures were deduced from extensive analyses of nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) data. metabolite anticipation using the online tool MetWork revealed the presence of a key and minor biosynthetic intermediates. These 18 compounds showed almost no cytotoxic effect up to 10 µM on human neuroblastoma SH-SY5Y and microglia BV2 cells, and some of them exhibited an interesting neuroprotective activity by reducing oxidative damage.
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http://dx.doi.org/10.3390/md17060319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627171PMC
May 2019

Tetrodotoxins Occurrence in Non-Traditional Vectors of the North Atlantic Waters (Portuguese Maritime Territory, and Morocco Coast).

Toxins (Basel) 2019 05 29;11(6). Epub 2019 May 29.

Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4619-007 Porto, Portugal.

Tetrodotoxin (TTX) is a potent alkaloid typically from tropical ecosystems, but in the last decade its presence has been more pronounced in the temperate waters of the Atlantic. In its last scientific opinion, the European Food Safety Authority (EFSA) stressed the need for data regarding TTX prevalence in European waters. To address EFSA's concerns, benthic organisms such as mollusks, crustaceans, echinoderms and fish with different feeding habits were collected along the Portuguese continental coast, islands (São Miguel, Azores, and Madeira) and the northwestern Moroccan coast. A total of 165 samples were analyzed by ultra high performance liquid chromatography high resolution mass spectrometry (UHPLC-HRMS) and ultra high performance chromatography mass spectrometry (UHPLC-MS/MS). Geographical tendencies were detected as follows, by descending order: S. Miguel Island (Azores), Moroccan coast, Madeira Island and Portuguese continental coast. The toxin amounts detected were significant, above the Dutch limit value established in 2017, showing the importance and the need for continuity of these studies to gain more knowledge about the prevalence of these toxins, unraveling new vectors, in order to better assess human health risk. This work represents a general overview of new TTX bearers (7) most of them in gastropods (, , and ), followed by echinoderms ( and ) and puffer fish .
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http://dx.doi.org/10.3390/toxins11060306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628425PMC
May 2019
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