An in situ bioadhesive foam as a large intestinal delivery platform for antibody fragment to treat inflammatory bowel disease.

Biologics have been widely used as injectables in the treatment of inflammatory bowel disease (IBD). Different local treatment attempts have been developed in recent years. However, maintaining systemic levels of biologics is still crucial for achieving colitis remission. An equilibrium between systemic and local concentrations of biologics is therefore essential for treatment of colitis. Current formulations struggle to create optimal balance between drug concentrations in plasma and the colonic wall. Addressing this challenge, we developed a rectally delivered in situ foam that generates CO2via a reaction between potassium bicarbonate (PB) and citric acid (CA) without the aid of an external device. An anti-TNF-α antibody fragment (Fab) was loaded into the foam formulation, which promoted prolonged colon retention and improved Fab distribution up to proximal colon following rectal administration to mice. In addition, we observed increased plasma Fab concentrations in mice receiving the rectal Fab foam compared to a Fab solution. In a non-everted rat gut ex vivo model, a single exposure to the CO2-containing foam improved macromolecule transepithelial flux across colonic tissue by over ten-fold. Foam efficacy for Fab was investigated in a range of colitis mouse models, from acute to chronic. This non-invasive formulation platform demonstrates potential to overcome existing limitations in delivering biologics to inflamed colonic tissue.

A short-term exposure to saxitoxin triggers a multitude of deleterious effects in Daphnia magna at levels deemed safe for human health.

Harmful algal blooms and the toxins produced during these events are a human and environmental health concern worldwide. Saxitoxin and its derivatives are potent natural aquatic neurotoxins produced by certain freshwater cyanobacteria and marine algae species during these bloom events. Saxitoxins effects on human health are well studied, however its effects on aquatic biota are still largely unexplored. This work aims at evaluating the effects of a pulse acute exposure (24 h) of the model cladoceran Daphnia magna to 30 µg saxitoxin L-1, which corresponds to the safety guideline established by the World Health Organization (WHO) for these toxins in recreational freshwaters. Saxitoxin effects were assessed through a comprehensive array of biochemical (antioxidant enzymes activity and lipid peroxidation), genotoxicity (alkaline comet assay), neurotoxicity (total cholinesterases activity), behavioral (swimming patterns), physiological (feeding rate and heart rate), and epigenetic (total 5-mC DNA methylation) biomarkers. Exposure resulted in decreased feeding rate, heart rate, total cholinesterases activity and catalase activity. Contrarily, other antioxidant enzymes, namely glutathione-S-transferases and selenium-dependent Glutathione peroxidase had their activity increased, together with lipid peroxidation levels. The enhancement of the antioxidant enzymes was not sufficient to prevent oxidative damage, as underpinned by lipid peroxidation enhancement. Accordingly, average DNA damage level was significantly increased in STX-exposed daphnids. Total DNA 5-mC level was significantly decreased in exposed organisms. Results showed that even a short-term exposure to saxitoxin causes significant effects on critical molecular and cellular pathways and modulates swimming patterns in D. magna individuals. This study highlights sub-lethal effects caused by saxitoxin in D. magna, suggesting that these toxins may represent a marked challenge to their thriving even at a concentration deemed safe for humans by the WHO.

Radiomic Pipelines for Prostate Cancer in External Beam Radiation Therapy: A Review of Methods and Future Directions.

Background: Prostate Cancer (PCa) is asymptomatic at an early stage and often painless, requiring only active surveillance. External Beam Radiotherapy (EBRT) is currently a curative option for localised and locally advanced diseases and a palliative option for metastatic low-volume disease. Although highly effective, especially in a hypofractionation scheme, 17.4% to 39.4% of all patients suffer from cancer recurrence after EBRT. But, radiographic findings also correlate with significant differences in protein expression patterns. In the PCa EBRT workflow, several imaging modalities are available for grading, staging and contouring. Using image data characterisation algorithms (radiomics), one can provide a quantitative analysis of prognostic and predictive treatment outcomes. Methods: This literature review searched for original studies in radiomics for PCa in the context of EBRT. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, this review includes 73 new studies and analyses datasets, imaging modality, segmentation technique, feature extraction, selection and model building methods. Results: Magnetic Resonance Imaging (MRI) is the preferred imaging modality for radiomic studies in PCa but Computed Tomography (CT), Positron Emission Tomography (PET) and Ultrasound (US) may offer valuable insights on tumour characterisation and treatment response prediction. Conclusions: Most radiomic studies used small, homogeneous and private datasets lacking external validation and variability. Future research should focus on collaborative efforts to create large, multicentric datasets and develop standardised methodologies, ensuring the full potential of radiomics in clinical practice.

Impact of chronic fluoxetine exposure on zebrafish: From fatty acid profile to behavior.

The consumption of antidepressants, such as fluoxetine, has increased over the years and, as a result, they are increasingly found in aquatic systems. Given the increasing use of zebrafish as an animal model in toxicological studies, this work proposed to evaluate the effects of chronic exposure, for 21 days, to fluoxetine at environmentally relevant concentrations (1, 10, 100, and 1000 ng/L). The behavioral tests performed did not reveal significant effects of fluoxetine. However, oxidative stress and changes in energy metabolism were detected after exposure to the highest concentrations of fluoxetine tested, namely a decrease in glutathione S-transferase (GST) activity (decrease of ca. 31%), increase in catalase (CAT) activity (increase of ca. 71%), and decrease in lactate dehydrogenase (LDH) activity (decrease of ca. 53%). Analysis of the fatty acid profile (FA) revealed a decrease in the omega-3 FA, docosahexaenoic acid (DHA), C22:6 (decrease in relative abundance between 6% and 8% for both the head and body), an increase in omega-6 FA, linoleic acid (LA), C18:2, (increased relative abundance between 8% and 11% in the head and between 5% and 9% in the body), which may suggest changes in the inflammatory state of these organisms. The integrated analysis adopted proved to be useful in detecting subindividual effects of fluoxetine and modes of action in fish.

Parental exposure to antidepressants has lasting effects on offspring? A case study with zebrafish.

Fish have common neurotransmitter pathways with humans, exhibiting a significant degree of conservation and homology. Thus, exposure to fluoxetine makes fish potentially susceptible to biochemical and physiological changes, similarly to what is observed in humans. Over the years, several studies demonstrated the potential effects of fluoxetine on different fish species and at different levels of biological organization. However, the effects of parental exposure to unexposed offspring remain largely unknown. The consequences of 15-day parental exposure to relevant concentrations of fluoxetine (100 and 1000 ng/L) were assessed on offspring using zebrafish as a model organism. Parental exposure resulted in offspring early hatching, non-inflation of the swimming bladder, increased malformation frequency, decreased heart rate and blood flow, and reduced growth. Additionally, a significant behavioral impairment was also found (reduced startle response, basal locomotor activity, and altered non-associative learning during early stages and a negative geotaxis and scototaxis, reduced thigmotaxis, and anti-social behavior at later life stages). These behavior alterations are consistent with decreased anxiety, a significant increase in the expression of the monoaminergic genes slc6a4a (sert), slc6a3 (dat), slc18a2 (vmat2), mao, tph1a, and th2, and altered levels of monoaminergic neurotransmitters. Alterations in behavior, expression of monoaminergic genes, and neurotransmitter levels persisted until offspring adulthood. Given the high conservation of neuronal pathways between fish and humans, data show the possibility of potential transgenerational and multigenerational effects of pharmaceuticals' exposure. These results reinforce the need for transgenerational and multigenerational studies in fish, under realistic scenarios, to provide realistic insights into the impact of these pharmaceuticals.

Effects of semaglutide-loaded lipid nanocapsules on metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disease that can progress to end-stage conditions with life-threatening complications, but no pharmacologic therapy has been approved. Drug delivery systems such as lipid nanocapsules (LNC) are very versatile platforms that are easy to produce and can induce the secretion of the native glucagon-like peptide 1 (GLP-1) when orally administered. GLP-1 analogs are currently being studied in clinical trials in the context of MASLD. Our nanosystem provides with increased levels of the native GLP-1 and increased plasmatic absorption of the encapsulated GLP-1 analog (semaglutide). Our goal was to use our strategy to demonstrate a better outcome and a greater impact on the metabolic syndrome associated with MASLD and on liver disease progression with our strategy compared with the oral marketed version of semaglutide, Rybelsus®. Therefore, we studied the effect of our nanocarriers on a dietary mouse model of MASLD, the Western diet model, during a daily chronic treatment of 4 weeks. Overall, the results showed a positive impact of semaglutide-loaded lipid nanocapsules towards the normalization of glucose homeostasis and insulin resistance. In the liver, there were no significant changes in lipid accumulation, but an improvement in markers related to inflammation was observed. Overall, our strategy had a positive trend on the metabolic syndrome and at reducing inflammation, mitigating the progression of the disease. Oral administration of the nanosystem was more efficient at preventing the progression of the disease to more severe states when compared to the administration of Rybelsus®, as a suspension.

Algorithms for Liver Segmentation in Computed Tomography Scans: A Historical Perspective.

Oncology has emerged as a crucial field of study in the domain of medicine. Computed tomography has gained widespread adoption as a radiological modality for the identification and characterisation of pathologies, particularly in oncology, enabling precise identification of affected organs and tissues. However, achieving accurate liver segmentation in computed tomography scans remains a challenge due to the presence of artefacts and the varying densities of soft tissues and adjacent organs. This paper compares artificial intelligence algorithms and traditional medical image processing techniques to assist radiologists in liver segmentation in computed tomography scans and evaluates their accuracy and efficiency. Despite notable progress in the field, the limited availability of public datasets remains a significant barrier to broad participation in research studies and replication of methodologies. Future directions should focus on increasing the accessibility of public datasets, establishing standardised evaluation metrics, and advancing the development of three-dimensional segmentation techniques. In addition, maintaining a collaborative relationship between technological advances and medical expertise is essential to ensure that these innovations not only achieve technical accuracy, but also remain aligned with clinical needs and realities. This synergy ensures their applicability and effectiveness in real-world healthcare environments.

Multilevel assessment of carbamazepine effects: An integrative approach using zebrafish early-life stages.

Carbamazepine (CBZ) is the most commonly used drug in epilepsy treatment, and its metabolites are commonly detected among persistent pharmaceuticals in the aquatic environment. This study aimed to investigate CBZ effects on early-life-stage zebrafish (Danio rerio) (from 2 to 168 hpf) by employing of an integrative approach linking endpoints from molecular to individual level: (i) development; (ii) locomotor activity; (iii) biochemical markers (lactate dehydrogenase, glutathione-S-transferase, acetylcholinesterase and catalase) and (iv) transcriptome analysis using microarray. A 168 h - LC50 of 73.4 mg L-1 and a 72 h - EC50 of 66.8 mg L-1 for hatching were calculated while developmental effects (oedemas and tail deformities) were observed at CBZ concentrations above 37.3 mg L-1. At the biochemical level, AChE activity proved to be the most sensitive parameter, as evidenced by its decrease across all concentrations tested (∼25% maximum reduction, LOEC (lowest observed effect concentration) < 0.6 µg L-1). Locomotor behaviour seemed to be depressed by CBZ although this effect was only evident at the highest concentration tested (50 mg L-1). Molecular analysis revealed a dose-dependent effect of CBZ on gene expression. Although only 25 genes were deregulated in organisms exposed to CBZ when compared to controls, both 0.6 and 2812 µg L-1 treatments impaired gene expression related to development (e.g. crygmxl1, org, klf2a, otos, stx16 and tob2) and the nervous system (e.g. Rtn3, Gdf10, Rtn3), while activated genes were associated with behavioural response (e.g. prlbr and taar). Altogether, our results indicate that environmentally relevant CBZ concentrations might affect biochemical and genetic traits of fish. Thus, the environmental risk of CBZ cannot be neglected, especially in a realistic scenario of constant input of domestic effluents into aquatic systems.

Biological responses in Danio rerio by the disinfectant SDBS in SARS-CoV-2 pandemic.

The use of disinfectants, such as Sodium Dodecylbenzene Sulfonic acid salt (SDBS), has grown since the SARS-CoV-2 pandemic, with environmentally unknown consequences. The present study analyzed SDBS effects in the fish species Danio rerio, using a combination of biomarkers. Our data reported that larvae had their total locomotor activity increased when exposed to 1 mg/L of SDBS, but this parameter was decreased in fish exposed to 5 mg/L. A significant increment of erratic movements was reported in fish exposed to 1 and 5 mg/L of SDBS. These concentrations inhibited CYP1A1/CYP1A2, and of GSTs inhibition, suggesting SDBS is not preferentially biotransformed by these routes. Results concerning the antioxidant defense biomarkers (CAT and GPx) showed no straightforward pattern, suggesting SDBS exposure may have resulted in changes in redox balance. Finally, acetylcholinesterase activity increased. In summary, increased use of SDBS in a near future may result in deleterious effects in environmentally exposed fish.

Changes in bryophyte functional composition during post-fire succession.

Climate and land-use changes are altering fire regimes in many regions around the world. To date, most studies have focused on the effects of altered fire regimes on woody and herbaceous communities, while the mechanisms driving post-fire bryophyte succession remain poorly understood, particularly in Mediterranean-type ecosystems. Here, we examined changes in bryophyte functional composition along a post-fire chronosequence (ranging from 1 to 20+ years) in Pyrenean oak woodlands (northeastern Portugal). To do so, we defined bryophyte functional groups based on seven morphological, reproductive, and life history traits. Then, we fitted linear and structural equation models to disentangle the direct and indirect effects of fire (time since fire and fire intensity), vegetation structure, climate, topography, and edaphic conditions on the abundance of each group. We identified two main functional groups: early colonizers (species with traits associated with strong colonization ability and desiccation tolerance) and perennial stayers (species with high competitive ability, i.e., large perennial mosses). Overall, the abundance of early colonizer species decreased with time since fire and increased with fire intensity, while the opposite was observed for perennial stayers. Thus, successional dynamics reflected a trade-off between species' competitive and colonization abilities, highlighting the role of biotic interactions later in succession. Patterns of functional composition were also consistent with changes in environmental conditions during succession, suggesting that species may experience stressful conditions (i.e., high radiation and low water availability) in early stages of post-fire succession. Our results also indicate that increased fire intensity may alter successional trajectories, leading to long-term changes in bryophyte communities. By understanding the response of bryophyte communities to fire, we were able to identify species with potential use as soil restoration materials.

"Green" synthesized versus chemically synthesized zinc oxide nanoparticles: In vivo antihyperglycemic activity and pharmacokinetics.

Zinc is one of the most studied trace elements, commonly used as supplement in diabetes treatment. By its involvement in the synthesis, secretion of insulin, promotion of insulin sensitivity and its multiple enzymatic functions it is known to contribute to reduce hyperglycemia. Researchers have shown that zinc administered under the form of zinc oxide nanoparticles (ZnONPs) is more effective than under its ionic form. Studies evaluating the antihyperglycemic activity of these nanocarriers include both ZnONPs synthesised using plants (i.e. green synthesized) or chemically synthesized. The present work aims to compare green synthesized ZnONPs with the marketed chemically synthesized ones. Green ZnONPs were synthesized using the aqueous extract of the stem bark of the medicinal plant Panda oleosa and zinc nitrate hexahydrate. Both nanocarriers were compared in terms of optical properties, morphology, composition, chemical functions, resistance to oxidation, in vivo antihyperglycemic activity via oral glucose tolerance test (OGTT) and pharmacokinetics in relation to zinc in C57BL/6J mice. A UV absorption peak was observed at 354 nm and 374 nm for the green and marketed ZnONPs, respectively. The shape and hydrodynamic diameters were anisotropic and of 228.8 ± 3.0 nm for the green ZnONPs and spherical and of 225.6 ± 0.9 nm for the marketed ZnONPs. Phenolic compounds accounted for 2.58 ± 0.04% of the green ZnONPs and allowed them to be more stable and unaffected by an oxidizing agent during the experiment, while the marketed chemically synthesized ZnONPs aggregated with or without contact with an oxidizing agent. No significant differences were observed on the amounts of zinc absorbed when comparing green ZnONPs, chemically synthesized ZnONPs and zinc sulfate in a pharmacokinetics study in normoglycemic mice. When evaluating the in vivo hypoglycemic activity of the nanocarriers in obese/diabetic mice, green synthesized ZnONPs displayed a significant hypoglycemic effect compared with the chemically synthesized nanoparticles following an OGTT. Altogether, these data indicate that phytocompounds, as catechin derivatives and polyphenols, attached to the green synthesized ZnONPs' surface, could contribute to their hypoglycemic activity. The comparison thus demonstrated that green synthesized ZnONPs are significantly more efficient than chemically ones at reducing hyperglycemia regardless of their absorption.

Influence of exposure scenario on the sensitivity to caffeine.

The chorion acts as a protective barrier, restricting some chemical absorption into the embryo and the surrounding fluids. In this sense, larvae may only have direct contact with some chemicals after dechorionation. This study aimed to evaluate the effects of caffeine (CAF) (0, 13, 20, 44, 67, and 100 mg.L-1) under different exposure scenarios (embryos with chorion or embryos/larvae already hatched) and rank the stage sensitivity. Thus, three scenarios were investigated: from 2 to 120 hours post fertilization (hpf) (5 days of exposure- 5dE), from 72 to 120 hpf (2dE), and from 96 to 120 hpf (1dE). Heart rate (48 hpf) and energy reserves (120 hpf) were measured in the 5dE scenario, and behavior and acetylcholinesterase (AChE) activity were evaluated at 120 hpf in all scenarios (5dE, 2dE, and 1dE). At 120 hpf, some of the fish was transferred to clean medium for a 10 days depuration period (10dPE). Behavior and AChE activity were assessed after this period. In the 5dE scenario, CAF increased heartbeat (13, 20, and 30 mg.L-1) and reduced carbohydrates (67, and 100 mg.L-1), while inhibiting AChE activity (100 mg.L-1) in the 5dE, 2dE, and 1dE scenarios. CAF reduced the total distance moved in the 5dE (67, and 100 mg.L-1), 2dE (20, 30, 44, 67, and 100 mg.L-1), and 1dE fish (67, and 100 mg.L-1) and increased erratic movements. Based on the lowest observed effect concentration (LOEC) for total distance moved (20 mg.L-1) and higher inhibition of AChE activity (100 mg.L-1) (65%), 2dE fish appear to be more sensitive to CAF. After 10dPE, a recovery in behavior was detected in all scenarios (5dE, 2dE, and 1dE). AChE activity remained inhibited in the 2dE scenario while increasing in the 1dE scenario. This study demonstrated that the presence of the chorion is an important factor for the analysis of CAF toxicity. After the loss of the chorion, organisms show greater sensitivity to CAF and can be used to evaluate the toxicity of various substances, including nanomaterials or chemicals with low capacity to cross the chorion. Therefore, the use of hatched embryos in toxicity tests is suggested, as they allow a shorter and less expensive exposure scenario that provides similar outcome as the conventional scenario.

Portuguese translation, cultural adaptation, and validation of the Person-Centred Practice Inventory - Staff (PCPI-S).

Aiming to translate, culturally adapt, and psychometrically evaluate the Person-centred Practice Inventory - Staff (PCPI-S) for Portuguese healthcare professionals, this methodological study was conducted sequentially in two phases. Phase I followed the 10-steps recommendations from the ISPOR taskforce for translation and cultural adaptation of patient reported outcome measures. Phase II comprised a quantitative cross-sectional virtual survey of the translated PCPI-S with healthcare professionals, who were reached through snowball sampling from both primary and specialized care settings. The psychometric properties of the PCPI-S were determined by assessing reliability and construct validity. A sample of 304 healthcare professionals participated in Phase II. Ceiling effects were found. The overall internal consistency was excellent (> 0.9). The confirmatory factor analysis showed a good model fit after minor modifications, revealing construct validity, and supporting the theoretical framework. In conclusion, the three-factorial model of PCPI-S adjusted to the studied sample is a valid and reliable instrument to assess the perceptions of healthcare professionals on person-centred practice in various Portuguese clinical contexts. Considering the ceiling effects, the effect of social desirability should be explored.

Portuguese translation, cultural adaptation, and validation of the Person-Centred Practice Inventory - Staff (PCPI-S) / Tradução, adaptação cultural e validação do Inventário da Prática Centrada na Pessoa, profissionais de saúde (PCPI-S)

Abstract Aiming to translate, culturally adapt, and psychometrically evaluate the Person-centred Practice Inventory - Staff (PCPI-S) for Portuguese healthcare professionals, this methodological study was conducted sequentially in two phases. Phase I followed the 10-steps recommendations from the ISPOR taskforce for translation and cultural adaptation of patient reported outcome measures. Phase II comprised a quantitative cross-sectional virtual survey of the translated PCPI-S with healthcare professionals, who were reached through snowball sampling from both primary and specialized care settings. The psychometric properties of the PCPI-S were determined by assessing reliability and construct validity. A sample of 304 healthcare professionals participated in Phase II. Ceiling effects were found. The overall internal consistency was excellent (> 0.9). The confirmatory factor analysis showed a good model fit after minor modifications, revealing construct validity, and supporting the theoretical framework. In conclusion, the three-factorial model of PCPI-S adjusted to the studied sample is a valid and reliable instrument to assess the perceptions of healthcare professionals on person-centred practice in various Portuguese clinical contexts. Considering the ceiling effects, the effect of social desirability should be explored.

Resumo Com o objetivo de traduzir, adaptar culturalmente e avaliar psicometricamente o Inventário para a Prática Centrada na Pessoa para profissionais de saúde (PCPI-S) em diversos contextos de prestação de cuidados, este estudo metodológico realizou-se em duas fases sequenciais. A Fase I seguiu as recomendações de dez etapas da taskforce da ISPOR para tradução e adaptação cultural de medidas de resultados auto reportados. A Fase II incluiu um estudo cross-sectional do PCPI-S traduzido com profissionais de saúde, que foram alcançados por meio de amostragem snowball em contextos de cuidados primários e diferenciados. A psicometria do PCPI-S foi analisada pela avaliação da confiabilidade e validade de construto. Uma amostra de 304 profissionais de saúde participou da Fase II. Efeitos de teto foram encontrados. A consistência interna geral foi excelente (> 0,9). A análise fatorial confirmatória mostrou um bom ajuste do modelo e validade de construto, refletindo o referencial teórico. Concluindo, o modelo tri-fatorial do PCPI-S ajustado à amostra estudada é um instrumento válido e fiável para avaliar as percepções dos profissionais de saúde sobre a prática centrada na pessoa em vários contextos de cuidados portugueses. Considerando os efeitos teto, a desejabilidade social deve ser explorada.

Behavioural, developmental and biochemical effects in zebrafish caused by ibuprofen, irgarol and terbuthylazine.

The increasing use of chemicals and their release into aquatic ecosystems are harming aquatic biota. Despite extensive ecotoxicological research, many environmental pollutants' ecological effects are still unknown. This study examined the spatial avoidance, behavioural and biochemical impacts of ibuprofen, irgarol, and terbuthylazine on the early life stages of zebrafish (Danio rerio) under a range of ecologically relevant concentrations (0-500 µg/L). Embryos were exposed following the OECD guideline "fish embryo toxicity test" complemented with biochemical assessment of AChE activity and behavioural analyses (swimming activity) using the video tracking system Zebrabox. Moreover, spatial avoidance was assessed by exposing 120 hpf-old larvae of D. rerio to a gradient of each chemical, by using the heterogeneous multi-habitat assay system (HeMHAS). The results obtained revealed that the 3 compounds delayed hatching at concentrations of 50 and 500 µg/L for both ibuprofen and irgarol and 500 µg/L for terbuthylazine. Moreover, all chemicals elicited a dose-dependent depression of movement (swimming distance) with LOEC values of 5, 500 and 50 µg/L for ibuprofen, irgarol and terbuthylazine, respectively. Zebrafish larvae avoided the three chemicals studied, with 4 h-AC50 values for ibuprofen, irgarol, and terbuthylazine of 64.32, 79.86, and 131.04 µg/L, respectively. The results of the HeMHAS assay suggest that larvae may early on avoid (just after 4 h of exposure) concentrations of the three chemicals that may later induce, apical and biochemical effects. Findings from this study make clear some advantages of using HeMHAS in ecotoxicology as it is: ecologically relevant (by simulating a chemically heterogeneous environmental scenario), sensitive (the perception of chemicals and the avoidance can occur at concentrations lower than those producing lethal or sublethal effects) and more humane and refined approach (organisms are not mandatorily exposed to concentrations that can produce individual toxicity).

Impact of environmentally relevant concentrations of fluoxetine on zebrafish larvae: From gene to behavior.

Fluoxetine is widely prescribed for the treatment of depressive states, acting at the level of the central nervous system, consequently affecting non-target organisms. This study aimed to investigate the influence of environmentally relevant fluoxetine concentrations (1-1000 ng/L) on Danio rerio development, assessing both embryotoxicity and behavior, antioxidant defense, gene expression and neurotransmitter levels at larval stage. Exposure to fluoxetine during early development was found to be able to accelerate embryo hatching in embryos exposed to 1, 10 and 100 ng/L, reduce larval size in 1000 ng/L, and increase heart rate in 10, 100 and 1000 ng/L exposed larvae. Behavioral impairments (decreased startle response and increased larvae locomotor activity) were associated with effects on monoaminergic systems, detected through the downregulation of key genes (vmat2, mao, tph1a and th2). In addition, altered levels of neurochemicals belonging to the serotonergic and dopaminergic systems (increased levels of tryptophan and norepinephrine) highlighted the sensitivity of early life stages of zebrafish to low concentrations of fluoxetine, inducing effects that may compromise larval survival. The obtained data support the necessity to test low concentrations of SSRIs in environmental risk assessment and the use of biomarkers at different levels of biological organization for a better understanding of modes of action.

Nonalcoholic fatty liver disease: Current therapies and future perspectives in drug delivery.

Nonalcoholic fatty liver disease (NAFLD) affects approximately 25% of the adult population worldwide. This pathology can progress into end-stage liver disease with life-threatening complications, and yet no pharmacologic therapy has been approved. NAFLD is commonly characterized by excessive fat accumulation in the liver and is in closely associated with insulin resistance and metabolic disorders, which suggests that NAFLD is the hepatic manifestation of metabolic syndrome. Regarding treatment options, the current validated strategy relies on lifestyle modifications (exercise and diet restrictions). Although there are no approved drug-based treatments, several clinical trials are ongoing. Novel targets are being discovered, and the repurposing of drugs that show promising effects in NAFLD is starting to gain more interest. The field of nanotechnology has been growing at an increasing rate, with new and more efficient drug delivery strategies being developed for NAFLD treatment. Nanocarriers can easily encapsulate drugs that need to be better protected from the organism to exert their effect or that need help at reaching their target, thereby helping achieve a better bioavailability. Drug delivery systems can also be designed to target the site of the disease, in this case, the liver. In this review, we focus on the current knowledge of NAFLD pathology, the targets being considered for clinical trials, and the current guidelines and ongoing clinical trials, with a specific focus on potential oral treatments for NAFLD using promising drug delivery strategies.

The role of temperature on zebrafish ontogenic development and sensitivity to pharmaceuticals.

This study assessed the effects of two emerging environmental pollutants caffeine (CAF) and metformin (METF) on juvenile zebrafish, raised at 22 °C or 27 ºC, after 96 h exposure. The temperature influenced the basal behaviour of unexposed juveniles, with higher swimming activity and a greater percentage of movements at the well edges observed in fish raised at 27 °C. A significant interaction between CAF and temperature was found for behavioural endpoints, but not for AChE activity, associated with neurotoxicity effects. CAF reduced swimming distance, increased erratic swimming, and inhibited AChE activity at 22 ºC, while at 27 ºC, CAF did not affect behaviour but increased AChE. METF exposure at 22 °C decreased swimming distance and increased erratic movements, but at 27 °C no effects were detected. Overall, temperature plays a more important role in the effects induced by CAF than METF.

A fish perspective on SARS-CoV-2: Toxicity of benzalkonium chloride on Danio rerio.

SARS-CoV-2 outbreak led to an increased marketing of disinfectants, creating a potential environmental problem. For instance, pre-pandemic environmental levels of the disinfectant benzalkonium chloride (BAC) ranging from 0.5 to 5 mgL-1 in effluents were expected to further increase threatening aquatic life. Our aim was to characterize potential adverse effects after an acute exposure of zebrafish to different concentrations of BAC. An increase in the overall swimming activity, thigmotaxis behavior, and erratic movements were observed. An increase in CYP1A1 and catalase activities, but inhibitions of CY1A2, GSTs and GPx activities were also noticed. BAC is metabolized by CYP1A1, increasing the production of H2O2, thereby activating the antioxidant enzyme CAT. Data also showed an increase of AChE activity. Our study highlights adverse embryonic, behavioral, and metabolic effects of noteworthy environmental significance, especially considering that the use and release of BAC is most likely to increase in a near future.

In Vitro Antiprotozoal Activity of Hibiscus sabdariffa Extract against a Ciliate Causing High Mortalities in Turbot Aquaculture.

Philasterides dicentrarchi is an histophagous parasite that infects flatfish, namely turbot (Scophthalmus maximus), and cause significant losses in aquaculture units. The available measures for P. dicentrarchi control have limited efficiency, and some cause harm to fish. Hence, sustainable and natural control strategies are urgently needed. This study evaluated the in vitro bioactivity of the ethanol extract of Hibiscus sabdariffa calyces on P. dicentrarchi population growth rate (PGR), oxidative stress biomarkers (glutathione-S-transferases (GST), glutathione reductase (GR), glutathione peroxidase (GPx), total glutathione (TG) and catalase (CAT), neurotoxicity (acetylcholinesterase, AChE), activity and gene expression of proteases as major virulence factors. H. sabdariffa extract inhibited parasite PGR (IC50 = 1.57 mg mL-1), and caused significant changes in the activity of antioxidant enzymes (LOEC = 0.22 mg mL-1), especially GPx, TG, and CAT. The activity of proteases was also severely inhibited (IC50 = 0.76 mg mL-1), and gene expression of catepsin 90 and leishmanolysin proteases was downregulated. Organic acids and phenolic phytochemicals in hibiscus extract are potentially responsible for the antiprotozoal bioactivity herein determined. Therefore, H. sabdariffa extract can be a promising disease-control alternative against the ciliate proliferation, cellular defense mechanisms and pathogenicity. Still, its applicability in aquaculture settings, and potential effects on farmed fish, should be further elucidated.