Protective effects of amphetamine and methylphenidate against dopaminergic neurotoxicants in SH-SY5Y cells.

Full treatment of the second most common neurodegenerative disorder, Parkinson's disease (PD), is still considered an unmet need. As the psychostimulants, amphetamine (AMPH) and methylphenidate (MPH), were shown to be neuroprotective against stroke and other neuronal injury diseases, this study aimed to evaluate their neuroprotective potential against two dopaminergic neurotoxicants, 6-hydroxydopamine (6-OHDA) and paraquat (PQ), in differentiated human dopaminergic SH-SY5Y cells. Neither cytotoxicity nor mitochondrial membrane potential changes were seen following a 24-hour exposure to either therapeutic concentration of AMPH or MPH (0.001-10 µM). On the other hand, a 24-hour exposure to 6-OHDA (31.25-500 µM) or PQ (100-5000 µM) induced concentration-dependent mitochondrial dysfunction, assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and lysosomal damage, evaluated by the neutral red uptake assay. The lethal concentrations 25 and 50 retrieved from the concentration-toxicity curves in the MTT assay were 99.9 µM and 133.6 µM for 6-OHDA, or 422 µM and 585.8 µM for PQ. Both toxicants caused mitochondrial membrane potential depolarization, but only 6-OHDA increased reactive oxygen species (ROS). Most importantly, PQ-induced toxicity was partially prevented by 1 µM of AMPH or MPH. Nonetheless, neither AMPH nor MPH could prevent 6-OHDA toxicity in this experimental model. According to these findings, AMPH and MPH may provide some neuroprotection against PQ-induced neurotoxicity, but further investigation is required to determine the exact mechanism underlying this protection.

Identification of key neuronal mechanisms triggered by dimethyl fumarate in SH-SY5Y human neuroblastoma cells through a metabolomic approach.

Dimethyl fumarate (DMF) is an old drug used for psoriasis treatment that has recently been repurposed to treat relapse-remitting multiple sclerosis, mostly due to its neuro- and immunomodulatory actions. However, mining of a pharmacovigilance database recently ranked DMF as the second pharmaceutical most associated with cognitive adverse events. To our best knowledge, the signaling mechanisms underlying its therapeutic and neurotoxic outcomes remain mostly undisclosed. This work thus represents the first-hand assessment of DMF-induced metabolic changes in undifferentiated SH-SY5Y human neuroblastoma cells, through an untargeted metabolomic approach using gas chromatography-mass spectrometry (GC-MS). The endometabolome was analyzed following 24 h and 96 h of exposure to two pharmacologically relevant DMF concentrations (0.1 and 10 µM). None of these conditions significantly reduced metabolic activity (MTT reduction assay). Our data showed that 24 h-exposure to DMF at both concentrations tested mainly affected metabolic pathways involved in mitochondrial activity (e.g., citric acid cycle, de novo triacylglycerol biosynthesis), and the synthesis of catecholamines and serotonin by changing the levels of their respective precursors, namely phenylalanine (0.68-fold decrease for 10 µM DMF vs vehicle), and tryptophan (1.36-fold increase for 0.1 µM DMF vs vehicle). Interestingly, taurine, whose levels can be modulated via Nrf2 signaling (DMF's primary target), emerged as a key mediator of DMF's neuronal action, displaying a 3.86-fold increase and 0.27-fold decrease for 10 µM DMF at 24 h and 96 h, respectively. A 96 h-exposure to DMF seemed to mainly trigger pathways associated with glucose production (e.g., gluconeogenesis, glucose-alanine cycle, malate-aspartate shuttle), possibly related to the metabolism of DMF into monomethyl fumarate and its further conversion into glucose via activation of the citric acid cycle. Overall, our data contribute to improving the understanding of the events associated with neuronal exposure to DMF.

Comparative In Vitro Study of the Cytotoxic Effects of Doxorubicin's Main Metabolites on Cardiac AC16 Cells Versus the Parent Drug.

Doxorubicin (DOX; also known as adriamycin) serves as a crucial antineoplastic agent in cancer treatment; however, its clinical utility is hampered by its' intrinsic cardiotoxicity. Although most DOX biotransformation occurs in the liver, a comprehensive understanding of the impact of DOX biotransformation and its' metabolites on its induced cardiotoxicity remains to be fully elucidated. This study aimed to explore the role of biotransformation and DOX's main metabolites in its induced cardiotoxicity in human differentiated cardiac AC16 cells. A key discovery from our study is that modulating metabolism had minimal effects on DOX-induced cytotoxicity: even so, metyrapone (a non-specific inhibitor of cytochrome P450) increased DOX-induced cytotoxicity at 2 µM, while diallyl sulphide (a CYP2E1 inhibitor) decreased the 1 µM DOX-triggered cytotoxicity. Then, the toxicity of the main DOX metabolites, doxorubicinol [(DOXol, 0.5 to 10 µM), doxorubicinone (DOXone, 1 to 10 µM), and 7-deoxydoxorubicinone (7-DeoxyDOX, 1 to 10 µM)] was compared to DOX (0.5 to 10 µM) following a 48-h exposure. All metabolites evaluated, DOXol, DOXone, and 7-DeoxyDOX caused mitochondrial dysfunction in differentiated AC16 cells, but only at 2 µM. In contrast, DOX elicited comparable cytotoxicity, but at half the concentration. Similarly, all metabolites, except 7-DeoxyDOX impacted on lysosomal ability to uptake neutral red. Therefore, the present study showed that the modulation of DOX metabolism demonstrated minimal impact on its cytotoxicity, with the main metabolites exhibiting lower toxicity to AC16 cardiac cells compared to DOX. In conclusion, our findings suggest that metabolism may not be a pivotal factor in mediating DOX's cardiotoxic effects.

Inflammation as common link to progressive neurological diseases.

Life expectancy has increased immensely over the past decades, bringing new challenges to the health systems as advanced age increases the predisposition for many diseases. One of those is the burden of neurologic disorders. While many hypotheses have been placed to explain aging mechanisms, it has been widely accepted that the increasing pro-inflammatory status with advanced age or "inflammaging" is a main determinant of biological aging. Furthermore, inflammaging is at the cornerstone of many age-related diseases and its involvement in neurologic disorders is an exciting hypothesis. Indeed, aging and neurologic disorders development in the elderly seem to share some basic pathways that fundamentally converge on inflammation. Peripheral inflammation significantly influences brain function and contributes to the development of neurological disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Understanding the role of inflammation in the pathogenesis of progressive neurological diseases is of crucial importance for developing effective treatments and interventions that can slow down or prevent disease progression, therefore, decreasing its social and economic burden.

The Role of Nrf2 and Inflammation on the Dissimilar Cardiotoxicity of Doxorubicin in Two-Time Points: a Cardio-Oncology In Vivo Study Through Time.

Doxorubicin (DOX) is a topoisomerase II inhibitor used in cancer therapy. Despite its efficacy, DOX causes serious adverse effects, such as short- and long-term cardiotoxicity. This work aimed to assess the short- and long-term cardiotoxicity of DOX and the role of inflammation and antioxidant defenses on that cardiotoxicity in a mice model. Adult CD-1 male mice received a cumulative dose of 9.0 mg/kg of DOX (2 biweekly intraperitoneal injections (ip), for 3 weeks). One week (1W) or 5 months (5M) after the last DOX administration, the heart was collected. One week after DOX, a significant increase in p62, tumor necrosis factor receptor (TNFR) 2, glutathione peroxidase 1, catalase, inducible nitric oxide synthase (iNOS) cardiac expression, and a trend towards an increase in interleukin (IL)-6, TNFR1, and B-cell lymphoma 2 associated X (Bax) expression was observed. Moreover, DOX induced a decrease on nuclear factor erythroid-2 related factor 2 (Nrf2) cardiac expression. In both 1W and 5M, DOX led to a high density of infiltrating M1 macrophages, but only the 1W-DOX group had a significantly higher number of nuclear factor κB (NF-κB) p65 immunopositive cells. As late effects (5M), an increase in Nrf2, myeloperoxidase, IL-33, tumor necrosis factor-α (TNF-α), superoxide dismutase 2 (SOD2) expression, and a trend towards increased catalase expression were observed. Moreover, B-cell lymphoma 2 (Bcl-2), cyclooxygenase-2 (COX-2), and carbonylated proteins expression decreased, and a trend towards decreased p38 mitogen-activated protein kinase (MAPK) expression were seen. Our study demonstrated that DOX induces adverse outcome pathways related to inflammation and oxidative stress, although activating different time-dependent response mechanisms.

The Metabolic Fingerprint of Doxorubicin-Induced Cardiotoxicity in Male CD-1 Mice Fades Away with Time While Autophagy Increases.

The cardiotoxicity of doxorubicin (DOX) may manifest at the beginning/during treatment or years after, compromising patients' quality of life. We intended to study the cardiac pathways one week (short-term, control 1 [CTRL1] and DOX1 groups) or five months (long-term, CTRL2 and DOX2 groups) after DOX administration in adult male CD-1 mice. Control groups were given saline, and DOX groups received a 9.0 mg/Kg cumulative dose. In the short-term, DOX decreased the content of AMP-activated protein kinase (AMPK) while the electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) increased compared to CTRL1, suggesting the upregulation of fatty acids oxidation. Moreover, mitofusin1 (Mfn1) content was decreased in DOX1, highlighting decreased mitochondrial fusion. In addition, increased B-cell lymphoma-2 associated X-protein (BAX) content in DOX1 pointed to the upregulation of apoptosis. Conversely, in the long-term, DOX decreased the citrate synthase (CS) activity and the content of Beclin1 and autophagy protein 5 (ATG5) compared to CTRL2, suggesting decreased mitochondrial density and autophagy. Our study demonstrates that molecular mechanisms elicited by DOX are modulated at different extents over time, supporting the differences on clinic cardiotoxic manifestations with time. Moreover, even five months after DOX administration, meaningful heart molecular changes occurred, reinforcing the need for the continuous cardiac monitoring of patients and determination of earlier biomarkers before clinical cardiotoxicity is set.

The role of inflammation and antioxidant defenses in the cardiotoxicity of doxorubicin in elderly CD-1 male mice.

Doxorubicin (DOX) is a potent chemotherapeutic agent used against several cancer types. However, due to its cardiotoxic adverse effects, the use of this drug may be also life-threatening. Although most cancer patients are elderly, they are poorly represented and evaluated in pre-clinical and clinical studies. Considering this, the present work aims to evaluate inflammation and oxidative stress as the main mechanisms of DOX-induced cardiotoxicity, in an innovative approach using an experimental model constituted of elderly animals treated with a clinically relevant human cumulative dose of DOX. Elderly (18-20 months) CD-1 male mice received biweekly DOX administrations, for 3 weeks, to reach a cumulative dose of 9.0 mg/kg. One week (1W) or two months (2 M) after the last DOX administration, the heart was collected to determine both drug's short and longer cardiac adverse effects. The obtained results showed that DOX causes cardiac histological damage and fibrosis at both time points. In the 1W-DOX group, the number of nuclear factor kappa B (NF-κB) p65 immunopositive cells increased and a trend toward increased NF-κB p65 expression was seen. An increase of inducible nitric oxide synthase (iNOS) and interleukin (IL)-33 and a trend toward increased IL-6 and B-cell lymphoma-2-associated X (Bax) expression were seen after DOX. In the same group, a decrease in IL-1ß, p62, and microtubule-associated protein 1A/1B-light chain 3 (LC3)-I, p38 mitogen-activated protein kinase (MAPK) expression was observed. Contrariwise, the animals sacrificed 2 M after DOX showed a significant increase in glutathione peroxidase 1 and Bax expression with persistent cardiac damage and fibrosis, while carbonylated proteins, erythroid-2-related factor 2 (Nrf2), NF-κB p65, myeloperoxidase, LC3-I, and LC3-II expression decreased. In conclusion, our study demonstrated that in an elderly mouse population, DOX induces cardiac inflammation, autophagy, and apoptosis in the heart in the short term. When kept for a longer period, oxidative-stress-linked pathways remained altered, as well as autophagy markers and tissue damage after DOX treatment, emphasizing the need for continuous post-treatment cardiac monitoring.

A Clinically Relevant Dosage of Mitoxantrone Disrupts the Glutathione and Lipid Metabolic Pathways of the CD-1 Mice Brain: A Metabolomics Study.

Long-term cognitive dysfunction, or "chemobrain", has been observed in cancer patients treated with chemotherapy. Mitoxantrone (MTX) is a topoisomerase II inhibitor that binds and intercalates with DNA, being used in the treatment of several cancers and multiple sclerosis. Although MTX can induce chemobrain, its neurotoxic mechanisms are poorly studied. This work aimed to identify the adverse outcome pathways (AOPs) activated in the brain upon the use of a clinically relevant cumulative dose of MTX. Three-month-old male CD-1 mice were given a biweekly intraperitoneal administration of MTX over the course of three weeks until reaching a total cumulative dose of 6 mg/kg. Controls were given sterile saline in the same schedule. Two weeks after the last administration, the mice were euthanized and their brains removed. The left brain hemisphere was used for targeted profiling of the metabolism of glutathione and the right hemisphere for an untargeted metabolomics approach. The obtained results revealed that MTX treatment reduced the availability of cysteine (Cys), cysteinylglycine (CysGly), and reduced glutathione (GSH) suggesting that MTX disrupts glutathione metabolism. The untargeted approach revealed metabolic circuits of phosphatidylethanolamine, catecholamines, unsaturated fatty acids biosynthesis, and glycerolipids as relevant players in AOPs of MTX in our in vivo model. As far as we know, our study was the first to perform such a broad profiling study on pathways that could put patients given MTX at risk of cognitive deficits.

Biodistribution and intestinal inflammatory response following voluntary oral intake of silver nanoparticles by C57BL/6J mice.

Silver nanoparticles (AgNP) are among the most widely commercialized nanomaterials globally, with applications in medicine and the food industry. Consequently, the increased use of AgNP in the food industry has led to an unavoidable rise  in human exposure to these nanoparticles. Their widespread use raises concerns about potential hazards to human health, specifically their intestinal pro-inflammatory effects. Thus, the main objective of this study was to evaluate the biological effects of two subacute doses of 5 nm polyvinylpyrrolidone (PVP)-AgNP in C57BL/6J mice. One mg/kg body weight or 10 mg/kg bw was provided once a day for 14 days, using a new technology (HaPILLness) that allows voluntary, stress-free, and accurate oral dosing. It was observed that after oral ingestion, while AgNP is biodistributed throughout the entire organism, most of the ingested dose is excreted in the feces. The passage and accumulation of AgNP throughout the intestine instigated a prominent inflammatory response, marked by significant histological, vascular, and cellular transformations. This response was driven by the activation of the nuclear factor-кB (NF-кB) inflammatory pathway, ultimately leading to the generation of multiple cytokines and chemokines.

Methodologies for Assessing Pancreatic Lipase Catalytic Activity: A Review.

Obesity is a disease of epidemic proportions with a concerning increasing trend. Regarded as one of the main sources of energy, lipids can also represent a big part of an unnecessary intake of calories and be, therefore, directly related to the problem of obesity. Pancreatic lipase is an enzyme that is essential in the absorption and digestion of dietary fats and has been explored as an alternative for the reduction of fat absorption and consequent weigh loss.Literature describes a great variability of methodologies and experimental conditions used in research to evaluate the in vitro inhibitory activity of compounds against pancreatic lipase. However, in an attempt to choose the best approach, it is necessary to know all the reaction conditions and understand how these can affect the enzymatic assay.The objective of this review is to understand and summarize the methodologies and respective experimental conditions that are mainly used to evaluate pancreatic lipase catalytic activity.156 studies were included in this work and a detailed description of the most commonly used UV/Vis spectrophotometric and fluorimetric instrumental techniques are presented, including a discussion regarding the differences found in the parameters used in both techniques, namely enzyme, substrate, buffer solutions, kinetics conditions, temperature and pH.This works shows that both UV/Vis spectrophotometry and fluorimetry are useful instrumental techniques for the evaluation of pancreatic lipase catalytic activity, presenting several advantages and limitations, which make the choice of parameters and experimental conditions a crucial decision to obtain the most reliable results.

Cardiac Molecular Remodeling by Anticancer Drugs: Doxorubicin Affects More Metabolism While Mitoxantrone Impacts More Autophagy in Adult CD-1 Male Mice.

Doxorubicin (DOX) and mitoxantrone (MTX) are classical chemotherapeutic agents used in cancer that induce similar clinical cardiotoxic effects, although it is not clear if they share similar underlying molecular mechanisms. We aimed to assess the effects of DOX and MTX on the cardiac remodeling, focusing mainly on metabolism and autophagy. Adult male CD-1 mice received pharmacologically relevant cumulative doses of DOX (18 mg/kg) and MTX (6 mg/kg). Both DOX and MTX disturbed cardiac metabolism, decreasing glycolysis, and increasing the dependency on fatty acids (FA) oxidation, namely, through decreased AMP-activated protein kinase (AMPK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) content and decreased free carnitine (C0) and increased acetylcarnitine (C2) concentration. Additionally, DOX heavily influenced glycolysis, oxidative metabolism, and amino acids turnover by exclusively decreasing phosphofructokinase (PFKM) and electron transfer flavoprotein-ubiquinone oxidoreductase (ETFDH) content, and the concentration of several amino acids. Conversely, both drugs downregulated autophagy given by the decreased content of autophagy protein 5 (ATG5) and microtubule-associated protein light chain 3 (LC3B), with MTX having also an impact on Beclin1. These results emphasize that DOX and MTX modulate cardiac remodeling differently, despite their clinical similarities, which is of paramount importance for future treatments.

Men's health care: concept analysis.

OBJECTIVES: To analyze the concept of men's health care and identify its essential, antecedent and consequent attributes in the health context. METHODS: This is a concept analysis structured in the theoretical-methodological framework of the Walker and Avant Model. An integrative review was carried out between May and July 2020, using keywords and descriptors: Men's Care and Health. RESULTS: The concept of men's health care is structured by 240 attributes, 14 categories, 82 antecedents and 159 consequents, from the selection of 26 published manuscripts. The design was evidenced from the dimensions: Intrapersonal, psychological and behavioral related to masculinities, interpersonal, organizational and structural, ecological, ethnoracial, cross-cultural and transpersonal. CONCLUSIONS: The concept of men's health care revealed the male specificities regarding the recognition of the place of health care and the daily exercise in the lived experience.

A Semi-Automatic Method for the Quantification of Astrocyte Number and Branching in Bulk Immunohistochemistry Images.

Immunohistochemical staining of cell and molecular targets in brain samples is a powerful tool that can provide valuable information on neurological mechanisms. However, post-processing of photomicrographs acquired after 3,3'-Diaminobenzidine (DAB) staining is particularly challenging due to the complexity associated with the size, samples number, analyzed targets, image quality, and even the subjectivity inherent to the analysis by different users. Conventionally, this analysis relies on the manual quantification of distinct parameters (e.g., the number and size of cells and the number and length of cell branching) in a large set of images. These represent extremely time-consuming and complex tasks, defaulting the processing of high amounts of information. Here we describe an improved semi-automatic method to quantify glial fibrillary acidic protein (GFAP)-labelled astrocytes in immunohistochemistry images of rat brains, at magnifications as low as 20×. This method is a straightforward adaptation of the Young & Morrison method, using ImageJ's plugin Skeletonize, coupled with intuitive data processing in datasheet-based software. It allows swifter and more efficient post-processing of brain tissue samples, regarding astrocyte size and number quantification, the total area occupied, as well as astrocyte branching and branch length (indicators of astrocyte activation), thus contributing to better understand the possible inflammatory response developed by astrocytes.

Men's health care: concept analysis / Cuidado de la salud de los hombres: análisis de concepto / Cuidado da saúde de homens: análise de conceito

Objective. To analyze the concept of men's health care and identify its essential, antecedent and consequent attributes in the health context. Methods. This is a concept analysis structured in the theoretical-methodological framework of the Walker and Avant Model. An integrative review was carried out between May and July 2020, using keywords and descriptors: Men's Care and Health. Results. The concept of men's health care is structured by 240 attributes, 14 categories, 82 antecedents and 159 consequents, from the selection of 26 published manuscripts. The design was evidenced from the dimensions: Intrapersonal, psychological and behavioral related to masculinities, interpersonal, organizational and structural, ecological, ethnoracial, cross-cultural and transpersonal. Conclusion. The concept of men's health care revealed the male specificities regarding the recognition of the place of health care and the daily exercise in the lived experience.

Objetivo. Analizar el concepto de cuidado de la salud de los hombres e identificar sus atributos esenciales, antecedentes y consecuencias en el contexto sanitario. Métodos. Se trata de un análisis conceptual estructurado en el marco teórico y metodológico del Modelo Walker y Avant. Se realizó una revisión integradora, mediante la utilización de palabras clave y descriptoras: Cuidado y Salud del Hombre. Resultados. El concepto de cuidado de la salud de los hombres está estructurado por 240 atributos, 14 categorías, 82 antecedentes y 159 consecuencias, originados en los 26 manuscritos publicados seleccionados. Se evidenció el delineamiento a partir de las dimensiones: Intrapersonal, psicológicas y conductuales relacionadas con las masculinidades, interpersonal, organizacional y estructural, ecológica, étnico-racial, transcultural y transpesonales. Conclusión. El concepto de cuidado de la salud de los hombres reveló las especificidades masculinas en cuanto al reconocimiento del lugar del cuidado de la salud y a su ejercicio cotidiano en la experiencia vivida.

Objetivo. Analisar o conceito do cuidado de saúde de homens e identificar respectivos atributos essenciais, antecedentes e consequentes no contexto sanitário. Métodos.Se trata de uma análise de conceito estruturado no referencial teórico-metodológico do Modelo de Walker e Avant. Se realizou uma revisão integrativa entre o mês de maio a julho de 2020, mediante a utilização de palavras chaves e descritores: Cuidado e Saúde do Homem. Resultados. O conceito de cuidado de saúde de homens está estruturado por 240 atributos, 14 categorias, 82 antecedentes e 159 consequentes, oriundos da seleção de 26 manuscritos publicados. Se evidenciou o delineamento a partir das dimensões: Intrapessoais, psicológicas e comportamentais relativas às masculinidades, interpessoais, organizacionais e estruturais, ecológicas, etnicoraciais, transculturais e transpessoais. Conclusão. O conceito de cuidado de saúde de homens revelou as especificidades masculinas quanto ao reconhecimento do lugar do cuidado de saúde e o seu exercício cotidiano na experiência vivida.

Post-COVID-19 metabolic syndrome: a new challenge for nursing care

In crisis scenarios, the professions that have the essence of caring for are highlighted. In this sense, during the COVID-19 pandemic, nursing played a key role in the identification, testing, care and rehabilitation of patients.(1) It was through this profession that many clients were fully assisted in the process of illness/rehabilitation, revealing the importance of the category for the health system; a fact that also persists in a post-COVID scenario. COVID-19 led to the collapse of global health with high rates of mortality and hospital morbidity, generating an estimated 18.2 million deaths around the world.(2) Nevertheless, it is known that COVID-19 is a respiratory disease with vascular implications that interact with cardiometabolic factors such as oxidative stress, endothelial dysfunction, insulin resistance, atherosclerosis, overweight, increased body fat and alterations in the microbiome, leading to systemic complications and death.(3)

Warmer water, high light intensity, lithium and microplastics: Dangerous environmental combinations to zooplankton and Global Health?

Nowadays there is a high concern about the combined effects of global warming and emerging environmental contaminants with significant increasing trends of use, such as lithium (Li) and microplastics (MPs), both on wildlife and human health. Therefore, the effects of high light intensity (26,000 lx) or warmer water temperature (25 °C) on the long-term toxicity of Li and mixtures of Li and MPs (Li-MPs mixtures) were investigated using model populations of the freshwater zooplankton species Daphnia magna. Three 21-day bioassays were done in the laboratory at the following water temperatures and light intensities: (i) 20 °C/10830 lx; (ii) 20 °C/26000 lx (high light intensity); (iii) 25 °C/10830 lx (warmer temperature). Based on the 21-day EC50s on reproduction, high light intensity increased the reproductive toxicity of Li and Li-MPs mixtures by ~1.3 fold; warmer temperature increased the toxicity of Li by ~1.2 fold, and the toxicity of Li-MPs mixtures by ~1.4 fold based on the concentration of Li, and by ~2 fold based on the concentrations of MPs. At high light intensity, Li (0.04 mg/L) and Li-MPs mixtures (0.04 Li + 0.09 MPs mg/L) reduced the population fitness by 32 % and 41 %, respectively. Warmer temperature, Li (0.05 mg/L) and Li-MPs mixtures (0.05 Li + 0.09 MPs mg/L) reduced it by 63 % and 71 %, respectively. At warmer temperature or high light intensity, higher concentrations of Li and Li-MPs mixtures lead to population extinction. Based on the population growth rate and using data of bioassays with MPs alone done simultaneously, Li and MPs interactions were antagonistic or synergistic depending on the scenario. High light intensity and chemical stress generally acted synergistically. Warmer temperature and chemical stress always acted synergistically. These findings highlight the threats of long-term exposure to Li and Li-MPs mixtures to freshwater zooplankton and Global Health in a warmer world.

Synthetic Cannabinoids: A Pharmacological and Toxicological Overview.

Synthetic cannabinoids (SCs) are a chemically diverse group of new psychoactive substances (NPSs) that target the endocannabinoid system, triggering a plethora of actions (e.g., elevated mood sensation, relaxation, appetite stimulation) that resemble, but are more intense than, those induced by cannabis. Although some of these effects have been explored for therapeutic applications, anticipated stronger psychoactive effects than cannabis and reduced risk perception have increased the recreational use of SCs, which have dominated the NPS market in the United States and Europe over the past decade. However, rising SC-related intoxications and deaths represent a major public health concern and embody a major challenge for policy makers. Here, we review the pharmacology and toxicology of SCs. A thorough characterization of SCs' pharmacodynamics and toxicodynamics is important to better understand the main mechanisms underlying acute and chronic effects of SCs, interpret the clinical/pathological findings related to SC use, and improve SC risk awareness.

Autophagy (but not metabolism) is a key event in mitoxantrone-induced cytotoxicity in differentiated AC16 cardiac cells.

Mitoxantrone (MTX) is an antineoplastic agent used to treat advanced breast cancer, prostate cancer, acute leukemia, lymphoma and multiple sclerosis. Although it is known to cause cumulative dose-related cardiotoxicity, the underlying mechanisms are still poorly understood. This study aims to compare the cardiotoxicity of MTX and its' pharmacologically active metabolite naphthoquinoxaline (NAPHT) in an in vitro cardiac model, human-differentiated AC16 cells, and determine the role of metabolism in the cardiotoxic effects. Concentration-dependent cytotoxicity was observed after MTX exposure, affecting mitochondrial function and lysosome uptake. On the other hand, the metabolite NAPHT only caused concentration-dependent cytotoxicity in the MTT reduction assay. When assessing the effect of different inhibitors/inducers of metabolism, it was observed that metyrapone (a cytochrome P450 inhibitor) and phenobarbital (a cytochrome P450 inducer) slightly increased MTX cytotoxicity, while 1-aminobenzotriazole (a suicide cytochrome P450 inhibitor) decreased fairly the MTX-triggered cytotoxicity in differentiated AC16 cells. When focusing in autophagy, the mTOR inhibitor rapamycin and the autophagy inhibitor 3-methyladenine exacerbated the cytotoxicity caused by MTX and NAPHT, while the autophagy blocker, chloroquine, partially reduced the cytotoxicity of MTX. In addition, we observed a decrease in p62, beclin-1, and ATG5 levels and an increase in LC3-II levels in MTX-incubated cells. In conclusion, in our in vitro model, neither metabolism nor exogenously given NAPHT are major contributors to MTX toxicity as seen by the residual influence of metabolism modulators used on the observed cytotoxicity and by NAPHT's low cytotoxicity profile. Conversely, autophagy is involved in MTX-induced cytotoxicity and MTX seems to act as an autophagy inducer, possibly through p62/LC3-II involvement.