Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer's disease through the antagonism of adenosine A2A receptors (A2ARs). To ...test if A2AR activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A2AR, we have developed a chimeric rhodopsin-A2AR protein (optoA2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A2AR to confer specific A2AR signaling. The specificity of the optoA2AR signaling was confirmed by light-induced selective enhancement of cAMP and phospho-mitogen-activated protein kinase (p-MAPK) (but not cGMP) levels in human embryonic kidney 293 (HEK293) cells, which was abolished by a point mutation at the C terminal of A2AR. Supporting its physiological relevance, optoA2AR activation and the A2AR agonist CGS21680 produced similar activation of cAMP and p-MAPK signaling in HEK293 cells, of p-MAPK in the nucleus accumbens and of c-Fos/phosphorylated-CREB (p-CREB) in the hippocampus, and similarly enhanced long-term potentiation in the hippocampus. Remarkably, optoA2AR activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while optoA2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A2AR signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A2AR signaling and functions depend on intracellular A2AR loops prompts the possibility of targeting the intracellular A2AR-interacting partners to selectively control different neuropsychiatric behaviors.
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•PE-MP are ingested by organisms representative of zooplanktonic marine taxa.•Virgin or BP-3 spiked PE-MP do not cause toxic effects on marine zooplankton.•BP-3 spiked PE-MP cause ...premature hatching of fish eggs compared with virgin PE-MP.•PE-MP do not pose remarkable environmental risk on marine plankton communities.
Toxicity of polyethylene microplastics (PE-MP) of size ranges similar to their natural food to zooplanktonic organisms representative of the main taxa present in marine plankton, including rotifers, copepods, bivalves, echinoderms and fish, was evaluated. Early life stages (ELS) were prioritized as testing models in order to maximize sensitivity. Treatments included particles spiked with benzophenone-3 (BP-3), a hydrophobic organic chemical used in cosmetics with direct input in coastal areas. Despite documented ingestion of both virgin and BP-3 spiked microplastics no acute toxicity was found at loads orders of magnitude above environmentally relevant concentrations on any of the invertebrate models. In fish tests some effects, including premature or reduced hatching, were observed after 12 d exposure at 10 mg L−1 of BP-3 spiked PE-MP. The results obtained do not support environmentally relevant risk of microplastics on marine zooplankton. Similar approaches testing more hydrophobic chemicals with higher acute toxicity are needed before these conclusions could be extended to other organic pollutants common in marine ecosystems. Therefore, the replacement of these polymers in consumer products must be carefully considered.
The use of probiotics to enhance intestinal health has been proposed for many years. Probiotics are traditionally defined as viable microorganisms that have a beneficial effect in the prevention and ...treatment of specific pathologic conditions when they are ingested. There is a relatively large volume of literature that supports the use of probiotics to prevent or treat intestinal disorders. However, the scientific basis of probiotic use has been firmly established only recently, and sound clinical studies have begun to be published. Currently, the best-studied probiotics are the lactic acid bacteria, particularly Lactobacillus sp. and Bifidobacterium sp. However, other organisms used as probiotics in humans include Escherichia coli, Streptococcus sp., Enterococcus sp., Bacteroides sp., Bacillus sp., Propionibacterium sp. and various fungi. Some probiotic preparations contain mixtures of more than one bacterial strain. Probiotics have been examined for their effectiveness in the prevention and treatment of a diverse spectrum of gastrointestinal disorders such as antibiotic-associated diarrhea (including Clostridium difficile-associated intestinal disease), infectious bacterial and viral diarrhea (including diarrhea caused by rotavirus, Shigella, Salmonella, enterotoxigenic E. coli, Vibrio cholerae and human immunodeficiency virus/acquired immunodeficiency disorder, enteral feeding diarrhea, Helicobacter pylori gastroenteritis, sucrase maltase deficiency, inflammatory bowel disease, irritable bowel syndrome, small bowel bacterial overgrowth and lactose intolerance. Probiotics have been found to inhibit intestinal bacterial enzymes involved in the synthesis of colonic carcinogens. There are many mechanisms by which probiotics enhance intestinal health, including stimulation of immunity, competition for limited nutrients, inhibition of epithelial and mucosal adherence, inhibition of epithelial invasion and production of antimicrobial substances. Probiotics represent an exciting prophylactic and therapeutic advance, although additional investigations must be undertaken before their role in intestinal health can be delineated clearly.
Imposex is a disorder caused by organotins, mainly tributyltin, which results in the appearance of male sexual characteristics in females of gastropod mollusks. The main objective of this work was to ...make a critical analysis of the relationship between imposex and butyltin body burdens in Nucella lapillus and Nassarius reticulatus. Specifically, this study evaluates possible additive effects among butyltins, proposes scales of effects based on robust statistical criteria as alternatives to existing ones and defines the body burdens of TBT in N. lapillus and N. reticulatus corresponding to the assessment classes (ACs) of the Vas Deferens Sequence Index (VDSI) established by OSPAR. Data of organotin body burdens and biological effects was retrieved from the ICES Dataset and from scientific literature. All responses, except the percentage of females displaying Imposex (IMPF) in Nucella lapillus, showed a sigmoidal profile regarding to the body burden of mono- (MBT), di- (DBT) and tributyltin and sum of butyltins (SumBTs). TBT and the SumBTs were better indicators of the VDSI or Relative Penis Size Index/Relative Penis Length Index (RPSI/RPLI) responses than MBT or DBT in most cases. From a statistical point of view, RPSI/RPLI and VDSI were better indicators of contamination by TBT than IMPF, although both RPSI and RPLI showed lower sensitivity than VDSI. The model used for describing the joint effect of butyltins provided a statistically significant fitting to the data assuming a null effect for both MBT and DBT for N. lapillus, and a lower toxic contribution of MBT and DBT with respect to TBT for N. reticulatus. RPSI or RPLI values, equivalent to the ACs for VDSI, were proposed as alternative criteria when measuring moderate to high levels of imposex. TBT concentrations in N. reticulatus and N. lapillus tissues, corresponding to the ACs were calculated and provided valuable information for cross-species comparisons.
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•The relationship between imposex and butyltin concentrations was analysed.•Data was retrieved from ICES Dataset and scientific literature.•The overall response profile observed for RPSI/RPLI or VDSI was sigmoidal.•Robust statistical criteria as alternatives to existing ones were proposed.•TBT concentrations corresponding to the assessment classes were calculated.
TBT concentrations in N. reticulatus and N. lapillus tissues, corresponding to the ACs were calculated and provided valuable information for cross-species comparisons.
Conventional plastics have become a major environmental concern due to their persistence and accumulation in marine ecosystems. The development of potential degradable polymers (PBP), such as ...polyhydroxyalkanoates (PHAs) and polylactic acid (PLA), has gained attention as an alternative to mitigate plastic pollution, since they have the potential to biodegrade under certain conditions, and their production is increasing as replacement of conventional polyolefins. This study aimed to assess and compare the toxicity of leachates of pre-compounding PBP (PLA and the PHA, polyhydroxybutyrate-covalerate (PHBv)) and polypropylene (PP) on five marine planktonic species. A battery of standard bioassays using bacteria, microalgae, sea urchin embryos, mussel embryos and copepod nauplii was conducted to assess the toxicity of leachates from those polymers. Additionally, the presence of chemical additives in the leachates was also verified through GC–MS and LC-HRMS analysis. Results showed that PHBv leachates exhibited higher toxicity compared to other polymers, with the microalgae Rhodomonas salina, being the most sensitive species to the tested leachates. On the other hand, PP and PLA generally displayed minimal to no toxicity in the studied species. Estimated species sensitivity distribution curves (SSD) show that PHBv leachates can be 10 times more hazardous to marine plankton than PP or PLA leachates, as demonstrated by the calculated Hazardous Concentration for 5 % of species (HC5). Qualitative chemical analysis supports the toxicological results, with 80 % of compounds being identified in PHBv leachates of which 2,4,6-trichlorophenol is worth mentioning due to the deleterious effects to aquatic biota described in literature. These findings underscore the fact that whereas environmental persistence can be targeted using PBP, the issue of chemical safety remains unsolved by some alternatives, such as PHBv. Gaining a comprehensive understanding of the toxicity profiles of PBP materials through a priori toxicological risk assessment is vital for their responsible application as alternatives to conventional plastics.
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•PHBv leachates caused acute toxic effects to all tested species.•PLA and PP exhibits lower toxicity than PHBv to the tested species.•A high number of harmful chemicals are identified in PHBv leachates.
Ghrelin is a metabolic hormone that has neuroprotective actions in a number of neurological conditions, including Parkinson's disease (PD), stroke and traumatic brain injury. Acyl ghrelin treatment ...in vivo and in vitro also shows protective capacity in Alzheimer's disease (AD). In the present study, we used ghrelin knockout (KO) and their wild‐type littermates to test whether or not endogenous ghrelin is protective in a mouse model of AD, in which human amyloid β peptide 1‐40 (Aβ1‐40) was injected into the lateral ventricles i.c.v. Recognition memory, using the novel object recognition task, was significantly impaired in ghrelin KO mice and after i.c.v. Aβ1‐40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Spatial orientation, as assessed by the Y‐maze task, was also significantly impaired in ghrelin KO mice and after i.c.v. Aβ1‐40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Ghrelin KO mice had deficits in olfactory discrimination; however, neither i.c.v. Aβ1‐40 treatment, nor acyl ghrelin injections affected olfactory discrimination. We used stereology to show that ghrelin KO and Aβ1‐40 increased the total number of glial fibrillary acidic protein expressing astrocytes and ionised calcium‐binding adapter expressing microglial in the rostral hippocampus. Finally, Aβ1‐40 blocked long‐term potentiation induced by high‐frequency stimulation and this effect could be acutely blocked with co‐administration of acyl ghrelin. Collectively, our studies demonstrate that ghrelin deletion affects memory performance and also that acyl ghrelin treatment may delay the onset of early events of AD. This supports the idea that acyl ghrelin treatment may be therapeutically beneficial with respect to restricting disease progression in AD.
Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer's disease through the antagonism of adenosine A.sub.2A receptors ...(A.sub.2ARs). To test if A.sub.2AR activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A.sub.2AR, we have developed a chimeric rhodopsin-A.sub.2AR protein (optoA.sub.2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A.sub.2AR to confer specific A.sub.2AR signaling. The specificity of the optoA.sub.2AR signaling was confirmed by light-induced selective enhancement of cAMP and phospho-mitogen-activated protein kinase (p-MAPK) (but not cGMP) levels in human embryonic kidney 293 (HEK293) cells, which was abolished by a point mutation at the C terminal of A.sub.2AR. Supporting its physiological relevance, optoA.sub.2AR activation and the A.sub.2AR agonist CGS21680 produced similar activation of cAMP and p-MAPK signaling in HEK293 cells, of p-MAPK in the nucleus accumbens and of c-Fos/phosphorylated-CREB (p-CREB) in the hippocampus, and similarly enhanced long-term potentiation in the hippocampus. Remarkably, optoA.sub.2AR activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while optoA.sub.2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A.sub.2AR signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A.sub.2AR signaling and functions depend on intracellular A.sub.2AR loops prompts the possibility of targeting the intracellular A.sub.2AR-interacting partners to selectively control different neuropsychiatric behaviors. Molecular Psychiatry (2015) 20, 1339-1349; doi: 10.1038/mp.2014.182; published online 17 February 2015
Data sets obtained from the quantitative analysis of 43 volatile organic compounds in air samples acquired every hour in 50 different sampling days (covering the different seasons) during the years ...2005 and 2006 in a suburban area of the NW Spain have been investigated by different chemometric methods including matrix augmentation principal component analysis (MA-PCA) and parallel factor analysis (PARAFAC). The application of these two chemometric methods allowed the estimation of the chemical profiles of the main pollution sources operating over the investigated location and also unravelling their main temporal patterns. Using PCA, it was possible to identify four main different sources related to different VOC families (aromatic, aliphatic, halogenated and biogenic). However, the temporal emission patterns could not be properly resolved when the data of each individual sampling day were considered separately. When VOC emissions during the same week and for the whole year (50 sampling days) were simultaneously analysed by a new matrix augmentation PCA (MA-PCA) strategy and by PARAFAC, a better recovery and description of the daily and hourly temporal trends were achieved. In fact, the combination of MA-PCA with the score rearrangement followed by the first singular value decomposition allowed the extraction of daily cyclical emission trends that were subjacent in the original non-trilinear data matrix by means of a very simple methodology facilitating the interpretation of these complex data sets.
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