Your search

Acetylcholinesterase (AChE) inhibitors are the primary target for single-molecule anti-Alzheimer’s disease (AD) therapeutics. Though AChE has historically been the focus of investigation for small-molecule inhibitors, interest in another cholinergic enzyme, butyrylcholinesterase (BChE), has grown in recent years. Attention stems from BChE’s role in β-amyloid (Aβ) protein aggregation and an increase in BChE concentration during the late stages of AD, where a decrease in AChE concentration is also observed. Currently, five FDA-approved drugs are on the market for inhibiting AChE, though no BChE-selective drugs have been approved so far. In this review, we focus on newly identified BChE selective inhibitors and present the ideas behind these discoveries. © 2025 by the authors.

The search for selective anticholinergic agents stems from varying cholinesterase levels as Alzheimer’s Disease progresses from the mid-to-late stage and from butyrylcholinesterase’s (BChE) role in β-amyloid plaque formation. While structure-based and pharmacophore-based virtual screening could search from large libraries in a short time, these methods do not consider dynamic features that result from a ligand’s inhibition of the enzyme and consequently may under- or overexaggerate enzyme selectivity of a given ligand. In this computational study, we probed the selectivity of representative secondary metabolite compounds against acetylcholinesterase and BChE through molecular dynamics simulations. The results were evaluated by analysis of the root mean squared deviation of ligand heavy atoms, the radius of gyration of each inhibited and uninhibited enzyme, root mean squared fluctuation of residues, intermolecular interaction energy, and linear interaction energy approximation of the Gibbs free energy of binding. These considerations further reveal the induced-fit characteristics contributing to ChE selectivity that are predominantly due to the greater flexibility of BChE’s active site gorge. © 2025 by the authors.

Sea lamprey (Petromyzon marinus) is a unique vertebrate model to examine how liver metabolomes support different reproductive functions. Juvenile sea lamprey prey on other fish species by attaching to their body and feeding on their blood and body fluids. Once reaching adulthood, they cease feeding, migrate to spawning streams and begin their final sexual maturation. During these processes, the male livers produce large quantities of bile acid pheromone precursors to be modified and released via gills, whereas the female livers synthesize vast amounts of vitellogenin (yolk lipophosphoprotein) to be transported to the ovary.

Migratory fishes are renowned for their ability to home to natal streams for spawning. Learned olfactory cues play a critical role in natal homing of Pacific salmon and other fishes, but the underlying chemical signature of streams remains poorly understood after decades of study. The molecules that convey a stream-specific odour must differ among sites but remain constant over time. Among leading odorant candidates are amino acids; however, little research has assessed the spatial and temporal variability of amino acid profiles in streams. We report a comprehensive chemical study of dissolved amino acids as potential olfactory cues for homing by migratory fish. Specifically, we profiled amino acids in water from 23 streams in the upper Laurentian Great Lakes basin over 2 years. We investigated variation in amino acid profiles (1) among regions and rivers within a year, (2) between years and (3) among sites and across the seasons of migration and early life history within a stream. Liquid-chromatography tandem mass spectrometry revealed nanomolar concentrations for most of the 20 L-amino acids measured, above the levels detectable by studied migratory fishes. Moreover, amino acid profiles were temporally stable between 2 years and across an annual season from adult spawning migration through offspring early-life development within a stream. However, spatial differences in amino acid profiles were evident primarily over large geographic distances (among regions) but not among tributaries within regions or among sites within a stream. Collectively, our results indicate dissolved amino acids may be consistent components of rivers' odorant profiles but suggest additional molecules are likely important for natal homing of migratory fishes to specific spawning sites. We suggest that future studies consider the combined importance of amino acids and molecules from other chemical classes. Understanding the chemical basis of olfactory-guided natal homing is especially important as human activities could alter the odorant profiles of streams and thereby disrupt fish migrations and negatively impact population recruitment.

Increasing concentrations of pharmaceutical compounds occur in many rivers, but their environmental risk remains poorly studied in stream biofilms. Flow intermittency shapes the structure and functions of ecosystems, and may enhance their sensitivity to toxicants. This study evaluates the effects of a long-term exposure of biofilm communities to a mixture of pharmaceutical compounds at environmental concentrations on biofilm bioaccumulation capacity, the structure and metabolic processes of algae and bacteria communities, and how their potential effects were enhanced or not by the occurrence of flow intermittency. To assess the interaction between those two stressors, an experiment with artificial streams was performed. Stream biofilms were exposed to a mixture of pharmaceuticals, as well as to a short period of flow intermittency. Results indicate that biofilms were negatively affected by pharmaceuticals. The algal biomass and taxa richness decreased and unicellular green algae relatively increased. The structure of the bacterial (based on denaturing gradient gel electrophoresis of amplified 16S rRNA genes) changed and showed a reduction of the operational taxonomic units (OTUs) richness. Exposed biofilms showed higher rates of metabolic processes, such as primary production and community respiration, attributed to pharmaceuticals stimulated an increase of green algae and heterotrophs, respectively. Flow intermittency modulated the effects of chemicals on natural communities. The algal community became more sensitive to short-term exposure of pharmaceuticals (lower EC50 value) when exposed to water intermittency, indicating cumulative effects between the two assessed stressors. In contrast to algae, the bacterial community became less sensitive to short-term exposure of pharmaceuticals (higher EC50) when exposed to water intermittency, indicating co-tolerance phenomena. According to the observed effects, the environmental risk of pharmaceuticals in nature is high, but different depending on the flow regime, as well as the target organisms (autotrophs vs heterotrophs).

Wastewater treatment plants (WWTPs) are one of the main sources of pharmaceuticals and endocrine disrupting compounds in freshwater ecosystems, and several studies have reported bioaccumulation of these compounds in different organisms in those ecosystems. River biofilms are exceptional indicators of pollution, but very few studies have focused on the accumulation of these emerging contaminants. The objectives of this study were first to develop an efficient analytical methodology for the simultaneous analysis of 44 pharmaceuticals and 13 endocrine disrupting compounds in biofilm, and second, to assess persistence, distribution, and bioaccumulation of these contaminants in natural biofilms inhabiting a WWTP-impacted river. The method is based on pressurized liquid extraction, purification by solid-phase extraction, and analysis by ultra performance liquid chromatography coupled to a mass spectrometer (UPLC–MS/MS) in tandem. Recoveries for pharmaceuticals were 31–137%, and for endocrine disruptors 32–93%. Method detection limits for endocrine disruptors were in the range of 0.2–2.4ngg−1, and for pharmaceuticals, 0.07–6.7ngg−1. A total of five endocrine disruptors and seven pharmaceuticals were detected in field samples at concentrations up to 100ngg−1.

Increasing evidence exists that emerging pollutants such as pharmaceuticals (PhACs) and endocrine-disrupting compounds (EDCs) can be bioaccumulated by aquatic organisms. However, the relative role of trophic transfers in the acquisition of emerging pollutants by aquatic organisms remains largely unexplored. In freshwater ecosystems, wastewater treatment plants are a major source of PhACs and EDCs. Here we studied the entrance of emerging pollutants and their flow through riverine food webs in an effluent-influenced river. To this end we assembled a data set on the composition and concentrations of a broad spectrum of PhACs (25 compounds) and EDCs (12 compounds) in water, biofilm, and three aquatic macroinvertebrate taxa with different trophic positions and feeding strategies (Ancylus fluviatilis, Hydropsyche sp., Phagocata vitta). We tested for similarities in pollutant levels among these compartments, and we compared observed bioaccumulation factors (BAFs) to those predicted by a previously-developed empirical model based on octanol–water distribution coefficients (Dow). Despite a high variation in composition and levels of emerging pollutants across food web compartments, observed BAFs in Hydropsyche and Phagocata matched, on average, those already predicted. Three compounds (the anti-inflammatory drug diclofenac, the lipid regulator gemfibrozil, and the flame retardant TBEP) were detected in water, biofilm and (at least) one macroinvertebrate taxa. TBEP was the only compound present in all taxa and showed magnification across trophic levels. This suggests that prey consumption may be, in some cases, a significant exposure route. This study advances the notion that both waterborne exposure and trophic interactions need to be taken into account when assessing the potential ecological risks of emerging pollutants in aquatic ecosystems.

The bioaccumulation of 20 pharmaceuticals in cockle (Cerastodema glaucum), noble pen shell (Pinna nobilis), sea snail (Murex trunculus), golden grey mullet (Liza aurata) and black goby (Gobius niger) was evaluated, considering their distribution throughout the Mar Menor lagoon and their variations in spring and autumn 2010. The analytical procedure was adapted for the different matrices as being sensitive and reproducible. Eighteen out of the 20 compounds analysed were found at low ngg−1 in these species throughout the lagoon. Hydrochlorothiazide and carbamazepine were detected in all species considered. The bioaccumulation of pharmaceuticals was heterogeneous in the lagoon, with a higher number of pharmaceuticals being detected in fish (18) than in wild molluscs (8), particularly in golden grey mullet muscle (16). В-blockers and psychiatric drugs were preferentially bioccumulated in fish and hydrochlorothiazide was also confirmed in caged clams. The higher detection frequency and concentrations found in golden grey mullet suggested that mugilids could be used as an indicator of contamination by pharmaceuticals in coastal areas. To the best of our knowledge, this is the first study that shows data about hydrochlorothiazide, levamisole and codeine in wild marine biota.

The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-specific uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals.

There is a growing interest in evaluating the presence of pharmaceutical residues and their metabolites in aquatic biota. In this study, twenty pharmaceuticals, including carbamazepine (CBZ) and two metabolites, were analyzed in homogenates of two fish species (Gambusia affinis and Jenynsia multidentata) captured in polluted areas of the Suquía River (Córdoba, Argentina). The twenty target pharmaceuticals were found in G. affinis, while only fifteen were detected in J. multidentata. We observed a noticeable difference in the accumulation pattern of both fish species, suggesting different pathways for the bioaccumulation of polar pharmaceuticals in each fish. In order to investigate uptake and tissue distribution of pharmaceuticals, a detailed study was performed under controlled laboratory conditions in J. multidentata, exposed to CBZ. CBZ and two of its metabolites (carbamazepine-10,11-epoxide – CBZ-EP and 2-hydroxycarbamazepine – 2-OH-CBZ) were monitored in five organs of fish under laboratory exposure. To our knowledge, this is the first report on the presence of CBZ and its metabolite 2-OH-CBZ in gills, intestine, liver, brain and muscle of fish, while the metabolite carbamazepine-10,11-epoxide (CBZ-EP) was detected in gills and muscle. A ratio CBZ-EP/CBZ close to 0.1 suggests that gills and muscle of J. multidentata could metabolize CBZ through the CBZ-EP pathway. Our results reinforce the need of analyzing multiple species to account for the environmental impact of pollutants, negating the simplification of a single, “representative model” during ecotoxicological biomonitoring. To our knowledge, the biotransformation of CBZ to its metabolites (CBZ-EP, 2-OH-CBZ) in fish, under controlled laboratory in vivo exposures, is reported for the first time.

Psychoactive drugs are frequently detected in the aquatic environment. The evolutionary conservation of the molecular targets of these drugs in fish suggests that they may elicit mode of action–mediated effects in fish as they do in humans, and the key open question is at what exposure concentrations these effects might occur. In the present study, the authors investigated the uptake and tissue distribution of the benzodiazepine oxazepam in the fathead minnow (Pimephales promelas) after 28 d of waterborne exposure to 0.8 μg L−1, 4.7 μg L−1, and 30.6 μg L−1. Successively, they explored the relationship between the internal concentrations of oxazepam and the effects on fish exploratory behavior quantified by performing 2 types of behavioral tests, the novel tank diving test and the shelter‐seeking test. The highest internal concentrations of oxazepam were found in brain, followed by plasma and liver, whereas muscle presented the lowest values. Average concentrations measured in the plasma of fish from the 3 exposure groups were, respectively, 8.7 ± 5.7 μg L−1, 30.3 ± 16.1 μg L−1, and 98.8 ± 72.9 μg L−1. Significant correlations between plasma and tissue concentrations of oxazepam were found in all 3 groups. Exposure of fish to 30.6 µg L−1 in water produced plasma concentrations within or just below the human therapeutic plasma concentration (HTPC) range in many individuals. Statistically significant behavioral effects in the novel tank diving test were observed in fish exposed to 4.7 μg L−1. In this group, plasma concentrations of oxazepam were approximately one‐third of the lowest HTPC value. No significant effects were observed in fish exposed to the lowest and highest concentrations. The significance of these results is discussed in the context of the species‐specific behavior of fathead minnow and existing knowledge of oxazepam pharmacology. Environ Toxicol Chem 2016;35:2782–2790. © 2016 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

We used a short-term microcosm approach to investigate the influence of two different subinhibitory concentrations of ciprofloxacin (0.01 and 0.1 μg/ml) on both the abundance of a plasmid-mediated quinolone resistance determinant (qnrS) and the structure and composition of bacterial communities from impaired and pristine water supply reservoirs. The results showed that the abundance of the qnrS gene increases in water samples exposed to both subinhibitory concentrations of ciprofloxacin, especially in water samples from La Llosa del Cavall, which represents the pristine system. Subinhibitory ciprofloxacin concentrations also induced changes in bacterial community composition as indicated by the relative abundances of each operational taxonomic unit (OTU) across treatments. Therefore, our findings may be of significant importance because subinhibitory ciprofloxacin concentrations may promote antibiotic resistance and affect bacterial community composition in environmental settings.

In many arid and semi-arid systems, biological communities in river ecosystems are submitted to flow interruption and desiccation, as well as to the impact of urban wastewaters. In this work, we studied (using a LC-LTQ-Orbitrap) the metabolomic response of biofilm communities exposed to both hydrological and chemical stressors. Fluvial biofilms were exposed to a mixture of 9 pharmaceuticals at a total concentration of 5000ng/L (mimicking concentrations and compounds found in polluted aquatic environments) and/or to seven days of desiccation, under laboratory conditions. The biosynthesis of fatty acids was the main metabolic pathway disrupted in biofilms. Endogenous biofilm's metabolites (metabolome) altered due to these stressors were identified. The metabolites that significantly changed only due to one of the stressors could be proposed as potential specific biomarkers. A biomarker of pharmaceutical exposure was the lysophosphatidic acid, which decreased a 160%, while for desiccation stearidonic acid (increased 160%), 16-Oxohexadecanoic acid (increased 340%) and palmitoleic acid (decreased 290%) were the biomarkers proposed. Besides, other metabolites showed different responses depending on the treatment, such as palmitic acid, linolenic acid, behenic acid, lignoceric acid and azelaic acid. The Carbon:Phosphorus (C:P) molar ratio increased due to all stress factors, whereas the algal community composition changed mainly due to desiccation. A possible relationship between those changes observed in structural parameters and the metabolome of biofilms was explored. Overall, our findings support the use of metabolomics to unravel at molecular level the effects from chemical and physical stressors on complex microbial communities, such as biofilms, and pinpoint biomarkers of exposure.

Recent species-extrapolation approaches to the prediction of the potential effects of pharmaceuticals present in the environment on wild fish are based on the assumption that pharmacokinetics and metabolism in humans and fish are comparable. To test this hypothesis, we exposed fathead minnows to the opiate pro-drug tramadol and examined uptake from the water into the blood and brain and the metabolism of the drug into its main metabolites. We found that plasma concentrations could be predicted reasonably accurately based on the lipophilicity of the drug once the pH of the water was taken into account. The concentrations of the drug and its main metabolites were higher in the brain than in the plasma, and the observed brain and plasma concentration ratios were within the range of values reported in mammalian species. This fish species was able to metabolize the pro-drug tramadol into the highly active metabolite O-desmethyl tramadol and the inactive metabolite N-desmethyl tramadol in a similar manner to that of mammals. However, we found that concentration ratios of O-desmethyl tramadol to tramadol were lower in the fish than values in most humans administered the drug. Our pharmacokinetic data of tramadol in fish help bridge the gap between widely available mammalian pharmacological data and potential effects on aquatic organisms and highlight the importance of understanding drug uptake and metabolism in fish to enable the full implementation of predictive toxicology approaches.

This study was aimed to determine the abundance of four antibiotic resistance genes (blaTEM, ermB, qnrS and sulI), as well as bacterial community composition associated with the intestinal mucus of wild freshwater fish species collected from the Foix and La Llosa del Cavall reservoirs, which represent ecosystems with high and low anthropogenic disturbance, respectively. Water and sediments from these reservoirs were also collected and analyzed to determine the pollution level by antibiotics. The blaTEM gene was only detected in brown trout and Ebro barbel, which were collected from La Llosa del Cavall reservoir. In contrast, the sulI and qnrS genes were only detected in common carp, which were collected from the Foix reservoir. Although the ermB gene was also detected in common carp, the values were below the limit of quantification. Likewise, water and sediment samples from the Foix reservoir had higher concentrations and more classes of antibiotics than those from La Llosa del Cavall. Pyrosequencing analysis of 16S rRNA genes revealed significant differences in bacterial communities associated with the intestinal mucus of fish species. Therefore, these findings suggest that anthropogenic activities are not only increasing the pollution of aquatic environments, but also contributing to the emergence and spread of antibiotic resistance in organisms that inhabit such environments.

Fish are good indicators of aquatic environment pollution because of their capability to uptake pollutants contained in water. Therefore, accumulation of pharmaceutical compounds in freshwater and marine fish and other aquatic organisms has been studied extensively in the last decade. In this context, the present study investigates the occurrence of pharmaceutical compounds in wild fish from 25 polluted river sites in the USA, downstream from wastewater treatment plants (WWTPs). Sample sites constitute a subset of urban rivers investigated in the U.S. EPA's 2008–2009 National Rivers and Streams Assessment. Thirteen pharmaceuticals (out of the twenty compounds analyzed) were quantified in fish fillets at concentrations commonly below 10ngg−1, in accordance with the findings from previous studies in the USA and Europe. The psychoactive drugs venlafaxine, carbamazepine and its metabolite 2-hydroxy carbamazepine were the most prevalent compounds (58%, 27% and 42%, respectively). This group of drugs is highly prescribed and rather resistant to degradation during conventional treatment in WWTPs as well as in natural aquatic environments. Salbutamol, a drug used to treat asthma, and the diuretic hydrochlorothiazide were also frequently detected (in >20% of the samples). Occurrence of six pharmaceutical families due to chronic exposure at environmental concentrations in water was detected in eight fish species.

This study investigated the occurrence of 135 contaminants of emerging concern (CECs) – pharmaceuticals, pesticides, a set of endocrine disrupting compounds (EDCs) (parabens, bisphenols, hormones, triazoles, organophosphorus flame retardants and triclosan), UV-filters, perfluoroalkyl substances (PFASs) and halogenated flame retardants (HFRs) – in 59 fish samples, collected in 2010 in 4 Spanish Rivers (Guadalquivir, Júcar, Ebro and Llobregat). Of the 135 CECs, 76 including 8 pharmaceuticals, 25 pesticides, 10 EDCs, 5 UV-filters, 15 PFASs and 13 HFRs were detected. Pharmaceuticals were the less frequently found and at lower concentrations. Pesticides, EDCs, UV-filters, PFASs and HFRs were detected more frequently (>50% of the samples). The maximum concentrations were 15 ng/g dry weight (dw) for pharmaceuticals (diclofenac), 840 ng/g dw for pesticides (chlorpyrifos), 224 ng/g dw for EDCs (bisphenol A), 242 ng/g dw for UV-filters (EHMC), 1738 ng/g dw for PFASs (PFHxA) and 64 ng/g dw for HFRs (Dec 602). The contaminants detected in fish are commonly detected also in sediments. In light of current knowledge, the risk assessment revealed that there was no risk for humans related to the exposure to CECs via freshwater fish consumption. However, results provide detailed information on the mixtures of CECs accumulated that would be very useful to identify their effects on aquatic biota.

Paullinia yoco R.E. Schult. & Killip (Sapindaceae) or 'yoco', is a liana (a woody vine) used traditionally by indigenous peoples of the upper Amazon region as a stimulating beverage, because it contains both caffeine and theobromine. However, as the wild plants become increasingly rare and hard to find because of permanent settlement within a much-reduced territory, there is growing interest among indigenous tribes to learn how to successfully cultivate it for community consumption and potentially as a cash crop. To date, there has been very little research conducted on the stimulant chemical composition of the liana and biochemical variation within- and between plants. This paper provides the results of chemical (high-performance liquid chromatography) analysis of caffeine and theobromine concentrations of multiple samples of phloem and leaf material from 18 Paullinia yoco lianas. Caffeine values ranged from 0.1% to 3.6% with a significantly higher amount in the stem phloem material than the leaf material, and there was a positive linear correlation between stem diameter and caffeine concentration (% dry weight). Although the highest theobromine level was found in leaf material (1.8%), overall there was no significant difference between phloem and leaf material, and no correlation between stem diameter and theobromine concentration. Finally, we found a significant amount of variance of both caffeine and theobromine between individual plants. These results are important, first because they shed light on the apparently conflicting previous reports on P. yoco caffeine and theobromine content; and second, they provide important clues about the phytochemical architecture of P. yoco which in turn has important implications for the design of a cultivation strategy for local indigenous communities to potentially produce a yet-to-be domesticated plant of substantial market potential.

Interest in the gender gap in the physical sciences has been ongoing for a number of years. This study aimed to explore differences in gender based on self-perception. The use of a post-examination survey was used to examine the role of gender in grade perception in chemistry courses over a several-year period. This included courses for non-science majors, health science majors, and traditional chemistry courses for science majors. Self-reported data was collected after the completion of examinations and analyzed to explore the connection between gender and the student’s postdiction (a prediction after the completion of the examination) of their examination score as it related to the Kruger-Dunning effect. While male and female students followed the same general patterns, it was found that for most students, male students tended to predict higher scores than female students while seeing little difference in actual performance. The lowest performing students (those scoring less than 50% on examinations) showed little difference in the accuracy of their postdictions based on gender. © 2024 National Science Teaching Association.

The search for selective anticholinergic agents stems from varying cholinesterase levels as Alzheimer’s Disease progresses from the mid to late stage. In this computational study, we probed the selectivity of FDA-approved and metabolite compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with molecular-docking-based virtual screening. The results were evaluated using locally developed codes for the statistical methods. The docking-predicted selectivity for AChE and BChE was predominantly the consequence of differences in the volume of the active site and the narrower entrance to the bottom of the active site gorge of AChE. © 2024 by the authors.