Cardiotoxicity and ROS Protection Assessment of three Structure-Related N-Acylhydrazones with Potential for the Treatment of Neurodegenerative Diseases.

The senescence process is associated with accumulated oxidative damage and increased metal concentration in the heart and brain. Besides, abnormal metal-protein interactions have also been linked with the development of several conditions, including Alzheimer's and Parkinson's diseases. Over the years we have described a series of structure-related compounds with different activities towards models of such diseases. In this work, we evaluated the potential of three N-acylhydrazones (INHHQ: 8-hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone, HPCIH: pyridine-2-carboxaldehyde isonicotinoyl hydrazone and X1INH: 1-methyl-1H-imidazole-2-carboxaldehyde isonicotinoyl hydrazone) to prevent oxidative stress in cellular models, with the dual intent of being active on this pathway and also to confirm their lack of cardiotoxicity as an important step in the drug development process, especially considering that the target population often presents cardiovascular comorbidity. The 8-hydroxyquinoline-contaning compound, INHHQ, exhibits a significant cardioprotective effect against hydrogen peroxide and a robust antioxidant activity. However, this compound is the most toxic to the studied cell models and seems to induce oxidative damage on its own. Interestingly, although not possessing a phenol group in its structure, the new-generation 1-methylimidazole derivative X1INH showed a cardioprotective tendency towards H9c2 cells, demonstrating the importance of attaining a compromise between activity and intrinsic cytotoxicity when developing a drug candidate.

Toxicological Effects of Fine Particulate Matter (PM2.5): Health Risks and Associated Systemic Injuries-Systematic Review.

Previous studies focused on investigating particulate matter with aerodynamic diameter ≤ 2.5 µm (PM2.5) have shown the risk of disease development, and association with increased morbidity and mortality rates. The current review investigate epidemiological and experimental findings from 2016 to 2021, which enabled the systemic overview of PM2.5's toxic impacts on human health. The Web of Science database search used descriptive terms to investigate the interaction among PM2.5 exposure, systemic effects, and COVID-19 disease. Analyzed studies have indicated that cardiovascular and respiratory systems have been extensively investigated and indicated as the main air pollution targets. Nevertheless, PM2.5 reaches other organic systems and harms the renal, neurological, gastrointestinal, and reproductive systems. Pathologies onset and/or get worse due to toxicological effects associated with the exposure to this particle type, since it can trigger several reactions, such as inflammatory responses, oxidative stress generation and genotoxicity. These cellular dysfunctions lead to organ malfunctions, as shown in the current review. In addition, the correlation between COVID-19/Sars-CoV-2 and PM2.5 exposure was also assessed to help better understand the role of atmospheric pollution in the pathophysiology of this disease. Despite the significant number of studies about PM2.5's effects on organic functions, available in the literature, there are still gaps in knowledge about how this particulate matter can hinder human health. The current review aimed to approach the main findings about the effect of PM2.5 exposure on different systems, and demonstrate the likely interaction of COVID-19/Sars-CoV-2 and PM2.5.

Assessment of the effects of seasonality on the ecotoxicity induced by the particulate matter using the animal model Caenorhabditis elegans.

The present work aimed to establish potential changes in the ecotoxicological effects on C. elegans induced by the exposure of coarse (PM10) and fine (PM2.5) particulate matter collected during dry and rainy periods. We also analyzed the probable influence on the change of a city's activities as the mega-events result in air quality. The element levels evaluation was performed on PM, on the solutions of exposure, and C. elegans after exposure. Biochemical essays were performed to evaluate damage to C. elegans. The results showed that infrastructure works increased the levels of pollutants, generating increases in the concentrations of PM2.5 and PM10. The biochemical results suggested effects mediated by different mechanisms, where PM2.5 induced an increase in antioxidant capacity with activation of the defense system and lipoperoxidation. Results suggest that PM10 reduces the antioxidant capacity and activates the glutathione S-transferase activity enzymatic action, but also induces lipoperoxidation in all groups of animals exposed to samples collected during the dry period of 2016. Individuals exposed to PM2.5 in 2017 wet and dry periods and PM10 in 2016 and 2017 dry periods shown a decrease in size compared to controls, while for fertility data, there was a decrease only in individuals exposed to PM2.5 in the periods that the highest levels of PM concentration. We conclude that despite the positive issues linked to the hosting of mega-events, their infrastructure requirements can compromise air quality and bring damage related to lipoperoxidation and physiological changes in the life cycle of biological systems, such as what happened to C. elegans exposed to tested extracts. Also, rainy events reduced the presence of these pollutants, washing the atmosphere.

Static Magnetic Stimulation Induces Changes in the Oxidative Status and Cell Viability Parameters in a Primary Culture Model of Astrocytes.

Astrocytes play an important role in the central nervous system function and may contribute to brain plasticity response during static magnetic fields (SMF) brain therapy. However, most studies evaluate SMF stimulation in brain plasticity while few studies evaluate the consequences of SMF at the cellular level. Thus, we here evaluate the effects of SMF at 305 mT (medium-intensity) in a primary culture of healthy/normal cortical astrocytes obtained from neonatal (1 to 2-day-old) Wistar rats. After reaching confluence, cells were daily subjected to SMF stimulation for 5 min, 15 min, 30 min, and 40 min during 7 consecutive days. Oxidative stress parameters, cell cycle, cell viability, and mitochondrial function were analyzed. The antioxidant capacity was reduced in groups stimulated for 5 and 40 min. Although no difference was observed in the enzymatic activity of superoxide dismutase and catalase or the total thiol content, lipid peroxidation was increased in all stimulated groups. The cell cycle was changed after 40 min of SMF stimulation while 15, 30, and 40 min led cells to death by necrosis. Mitochondrial function was reduced after SMF stimulation, although imaging analysis did not reveal substantial changes in the mitochondrial network. Results mainly revealed that SMF compromised healthy astrocytes' oxidative status and viability. This finding reveals how important is to understand the SMF stimulation at the cellular level since this therapeutic approach has been largely used against neurological and psychiatric diseases.

The impact of polar fraction of the fine particulate matter on redox responses in different rat tissues.

Particulate matter (PM) contains different chemical substances that have been associated with health effects and an increased risk of mortality due to their toxicity. In this study, fine particulate matter (PM2.5) samples were collected in a region with rural characteristics (Seropédica (Se)) and another with some industries (Duque de Caxias (DC)) (Brazil, RJ). Rats were exposed to PM2.5 extracts daily for 25 days at different dilutions: 10×, 5×, and a concentrated solution (CS). Biochemical analyses were investigated for total antioxidant capacity (ACAP), lipid peroxidation (LPO) levels, reduced glutathione (GSH) concentration, activity of glutamate cysteine ligase (GCL), and activity of glutathione S-transferase (GST). The liver showed a significant increase in GCL (DC-5×, DC-CS and Se-CS) and GST activities (DC-CS and Se-CS) in both regions when compared to the control group. In the renal cortex, GCL activity decreased in most of the tested groups while GST activity increased only in the 5× groups of both regions (DC and Se). In the renal medulla, GCL activity decreased for Se-10× and DC-CS but increased for Se-5×, and GST activity increased in the Se-10×, DC-5×, and DC-CS groups. Lung GCL increased in all groups for both regions. Moreover, this organ also showed an increase in GST activity when higher metal concentrations were present (5× and CS). TBARS levels were increased for all tissues in most tested concentrations. These data indicate that soluble compounds (e.g., metals) from PM2.5 sampled in areas with different pollution indexes can change the redox status and cause damage to different tissues.

Toxicological effects of particulate matter (PM2.5) on rats: Bioaccumulation, antioxidant alterations, lipid damage, and ABC transporter activity.

Previous studies have demonstrated the harmful effects of atmospheric pollutants on cardiac systems because of the presence of particulate matter (PM), a complex mixture of numerous substances including trace metals. In this study, the toxicity of PM2.5 from two regions, rural (PM2.5 level of 8.5 ± 4.0 µg m(-3)) and industrial (PM2.5 level of 14.4 ± 4.1 µg m(-3)) in Brazil, was investigated through in vivo experiments in rats. Metal accumulation and biochemical responses were evaluated after rats were exposed to three different concentrations of PM2.5 in saline extract (10× dilution, 5× dilution, and concentrated). The experimental data showed the bioaccumulation of diverse trace metals in the hearts of groups exposed to PM2.5 from both regions. Furthermore, mobilization of the antioxidant defenses and an increase in lipid peroxidation of the cardiac tissue was observed in response to the industrial and rural area PM2.5. Glutathione-S-transferase activity was increased in groups exposed to the 5× and concentrated rural PM2.5. Additionally, ATP-binding cassette (ABC) transporter activity in the cardiac tissue exposed to PM2.5 was reduced in response to the 5× dilution of the rural and industrial region PM2.5. Histological analysis showed a decrease in the percentage of cardiac cells in the heart at all tested concentrations. The results indicate that exposure to different concentrations of PM2.5 from both sources causes biochemical and histological changes in the heart with consequent damage to biological structures; these factors can favor the development of cardiac diseases.

Glyphosate on digestive enzymes activity in piava (Leporinus obtusidens) / Glifosato sobre a atividade de enzimas digestivas em piavas (Leporinus obtusidens)

The effects of glyphosate, a nonselective herbicide (1.0 or 5.0mg L-1) on digestive enzymes activity (stomach and intestine) were evaluated in juveniles of piava (Leporinus obtusidens) after 90 days of exposure. The activity of acid protease, trypsin, chymotrypsin and amylase increased with the increase of glyphosate concentration. These results indicate that glyphosate affects digestive enzyme activities in this species, and may be an indicator of poor nutrient availability when fish survive in herbicide-contaminated water.

Os efeitos do glifosato, um herbicida não seletivo (1,0 ou 5,0mg L-1), sobre a atividade de enzimas digestivas (estômago e intestino) foram avaliadas em juvenis de piava (Leporinus obtusidens) após 90 dias de exposição. A atividade da protease ácida, tripsina, quimiotripsina e amilase aumentaram com a elevação da concentração de glifosato. Esses resultados indicam que o glifosato afeta a atividade de enzimas digestivas nesta espécie e pode ser indicador da reduzida disponibilidade de nutrientes, quando peixes sobrevivem em água contaminada com este herbicida.

Exposure to sublethal concentrations of copper changes biochemistry parameters in silver catfish, Rhamdia quelen, Quoy & Gaimard.

The effects of Cu exposure on catalase (CAT) and acetylcholinesterase (AChE) activity, formation of thiobarbituric acid-reactive species (TBARS) and metabolic parameters were evaluated in silver catfish (Rhamdia quelen). The fish were exposed for 45 days to 0, 16 and 29 µg/L Cu. The fish that were exposed to Cu exhibited lower TBARS levels in the muscle and higher TBARS levels in the liver. They also showed lower CAT activity in the liver and lower AChE activity in the brain and muscle. Higher glucose and lactate and lower protein plasma levels were observed in the fish exposed to Cu. The changes in the hepatic metabolic parameters were Cu concentration dependent. In the muscle, lower glycogen and higher lactate levels were observed in the fish exposed to Cu. Alterations in the metabolic parameters showed a preference for the anaerobic pathway of energy production and liver protein catabolism to supply the energy demand.

Sublethal zinc and copper exposure affect acetylcholinesterase activity and accumulation in different tissues of Leporinus obtusidens.

In this study, we investigated zinc and copper effects on acetylcholinesterase (AChE, EC. 3.1.1.7) activity and metal accumulation in tissues of native fish Leporinus obtusidens (piava). Fish were exposed to 10 and 20 % of the LC(50) that corresponded at 2.28 and 4.57 mg/L (zinc) and 0.018 and 0.038 mg/L (copper) for 30 and 45 days. The AChE activity was evaluated in brain and white muscle of fish and metals accumulation was measured in kidney, liver, muscle and brain. Exposure to zinc and copper significantly increased AChE activity in both tissues and times tested, except for brain AChE activity at 2.28 mg/L of Zn (II) after 45 days where a reduction of 52.5 % was observed. Fish exposed to zinc showed accumulation of this metal in liver and kidney in both concentrations and times tested. A different result was obtained for copper: significant copper accumulation was obtained only in brain at both concentrations tested after 45 days of exposure. These results suggest that piavas exposed to zinc and copper showed changes in AChE activity and also demonstrate accumulation in some tissues. These results demonstrate that L. obtusidens could be a good bioindicator to evaluate water containing metals. The metal accumulation absence in muscle tissue is an indicative of low potential contamination by metals in this fish species.

Swim training does not protect mice from skeletal muscle oxidative damage following a maximum exercise test.

We investigated whether swim training protects skeletal muscle from oxidative damage in response to a maximum progressive exercise. First, we investigated the effect of swim training on the activities of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), in the gastrocnemius muscle of C57Bl/6 mice, 48 h after the last training session. Mice swam for 90 min, twice a day, for 5 weeks at 31°C (± 1°C). The activities of SOD and CAT were increased in trained mice (P < 0.05) compared to untrained group. However, no effect of training was observed in the activity of GPx. In a second experiment, trained and untrained mice were submitted to a maximum progressive swim test. Compared to control mice (untrained, not acutely exercised), malondialdehyde (MDA) levels were increased in the skeletal muscle of both trained and untrained mice after maximum swim. The activity of GPx was increased in the skeletal muscle of both trained and untrained mice, while SOD activity was increased only in trained mice after maximum swimming. CAT activity was increased only in the untrained compared to the control group. Although the trained mice showed increased activity of citrate synthase in skeletal muscle, swim performance was not different compared to untrained mice. Our results show an imbalance in the activities of SOD, CAT and GPx in response to swim training, which could account for the oxidative damage observed in the skeletal muscle of trained mice in response to maximum swim, resulting in the absence of improved exercise performance.

Cardiac oxidative stress is involved in heart failure induced by thiamine deprivation in rats.

Thiamine is an important cofactor of metabolic enzymes, and its deficiency leads to cardiovascular dysfunction. First, we characterized the metabolic status measuring resting oxygen consumption rate and lactate blood concentration after 35 days of thiamine deficiency (TD). The results pointed to a decrease in resting oxygen consumption and a twofold increase in blood lactate. Confocal microscopy showed that intracellular superoxide (approximately 40%) and H(2)O(2) (2.5 times) contents had been increased. In addition, biochemical activities and protein expression of SOD, glutathione peroxidase, and catalase were evaluated in hearts isolated from rats submitted to thiamine deprivation. No difference in SOD activity was detected, but protein levels were found to be increased. Catalase activity increased 2.1 times in TD hearts. The observed gain in activity was attended by an increased catalase protein level. However, a marked decrease in glutathione peroxidase activity (control 435.3 + or - 28.6 vs. TD 199.4 + or - 30.2 nmol NADPH x min(-1) x ml(-1)) was paralleled by a diminution in the protein levels. Compared with control hearts, we did observe a greater proportion of apoptotic myocytes by TdT-mediated dUTP nick end labeling (TUNEL) and caspase-3 reactivity techniques. These results indicate that during TD, reactive oxygen species (ROS) production may be enhanced as a consequence of the installed acidosis. The perturbation in the cardiac myocytes redox balance was responsible for the increase in apoptosis.

Herbicide formulation with glyphosate affects growth, acetylcholinesterase activity, and metabolic and hematological parameters in piava (Leporinus obtusidens).

The teleost fish Leporinus obtusidens (piava) was exposed to different concentrations of Roundup, a commercial herbicide formulation containing glyphosate (0, 1, or 5 mg L(-1)), for 90 days. Acetylcholinesterase (AChE) activity was verified in brain and muscle. Hepatic and muscular metabolic parameters as well as some hematological parameters were determined. The results showed that brain AChE activity was significantly decreased in fish exposed to 5 mg L(-1) Roundup, whereas muscular AChE activity was not altered. Both Roundup concentrations significantly decreased liver glycogen without altering the muscle glycogen content. Hepatic glucose levels were reduced only in fish exposed to 5 mg L(-1) Roundup. Lactate levels in the liver and muscle significantly increased in fish exposed to both Roundup concentrations. Hepatic protein content remained constant at 1 mg L(-1) but increased at 5 mg L(-1) Roundup. In the muscle however, protein content decreased with increasing exposure concentration. The herbicide exposure produced a decrease in hematological parameters at both concentrations tested. The majority of observed effects occur at environmental relevant concentrations, and in summary, the results show that Roundup affects brain AChE activity as well as metabolic and hematologic parameters of piavas. Thus, we can suggest that long-term exposure to Roundup causes metabolic disruption in Leporinus obtusidens.