The administration of methyl and butyl parabens interferes with the enzymatic antioxidant system and induces genotoxicity in rat testis: possible relation to male infertility.

Parabens are esters of p-hydroxybenzoic acid, used for decades as a preservative in many products, including agrochemicals, pharmaceuticals, foods and cosmetics. Concerns regarding parabens toxicity include adverse effects on endocrine activity, carcinogenesis, infertility, spermatogenesis, and adipogenesis. The present study aimed to investigate the in vivo administration of methyl and butylparaben at concentrations of 100 and 200 mg/kg body weight, by subcutaneous injection, in variable murinometric measurements, antioxidant systems and genotoxicity. The administration of parabens did not affect the consumption of water and food. However, there was a decrease in the weight of the testes and the seminal vesicle (p < 0.05). The administration of parabens caused an increase in superoxide dismutase for methylparaben (200 mg/kg) and both concentrations of butylparaben (p < 0.05). Catalase showed increased activity in all groups treated with parabens. In contrast, glutathione reductase and glutathione S-transferase suffered a decrease in the groups treated with both parabens. These results show that parabens, especially butyl, can affect the rat testis enzymatic antioxidant system, decreasing the cellular antioxidant capacity, which was confirmed by the decrease in the glutathione reducing power, expressed by the reduced glutathione/oxidized glutathione ratio. Therefore, an increase in lipid peroxidation was observed, which was significant in the case of butyl. Genetic Damage Indicator values show that butylparaben treatments displayed significantly higher values than the control. This study shows for the first time that parabens can induce genotoxicity in the rat male reproductive organ.

Mitochondrial Dysfunction in Skeletal Muscle of Rotenone-Induced Rat Model of Parkinson's Disease: SC-Nanophytosomes as Therapeutic Approach.

The development of new therapeutic options for Parkinson's disease (PD) requires formulations able to mitigate both brain degeneration and motor dysfunctions. SC-Nanophytosomes, an oral mitochondria-targeted formulation developed with Codium tomentosum membrane polar lipids and elderberry anthocyanin-enriched extract, promote significant brain benefits on a rotenone-induced rat model of PD. In the present work, the effects of SC-Nanophytosome treatment on the skeletal muscle tissues are disclosed. It is unveiled that the rotenone-induced PD rat model exhibits motor disabilities and skeletal muscle tissues with deficient activity of mitochondrial complexes I and II along with small changes in antioxidant enzyme activity and skeletal muscle lipidome. SC-Nanophytosome treatment mitigates the impairment of complexes I and II activity, improving the mitochondrial respiratory chain performance at levels that surpass the control. Therefore, SC-Nanophytosome competence to overcome the PD-related motor disabilities should be also associated with its positive outcomes on skeletal muscle mitochondria. Providing a cellular environment with more reduced redox potential, SC-Nanophytosome treatment improves the skeletal muscle tissue's ability to deal with oxidative stress stimuli. The PD-related small changes on skeletal muscle lipidome were also counteracted by SC-Nanophytosome treatment. Thus, the present results reinforces the concept of SC-Nanophytosomes as a mitochondria-targeted therapy to address the neurodegeneration challenge.

Brain Effects of SC-Nanophytosomes on a Rotenone-Induced Rat Model of Parkinson's Disease-A Proof of Concept for a Mitochondria-Targeted Therapy.

Mitochondria are an attractive target to fight neurodegenerative diseases due to their important functions for cells and the particularly close relationship between the functional connectivity among brain regions and mitochondrial performance. This work presents a mitochondria-targeted therapy designed to modulate the functionality of the mitochondrial respiratory chain and lipidome, parameters that are affected in neurodegeneration, including in Parkinson's disease (PD). This therapy is supported by SC-Nanophytosomes constructed with membrane polar lipids, from Codium tomentosum, and elderberry anthocyanin-enriched extract, from Sambucus nigra L. SC-Nanophytosomes are nanosized vesicles with a high negative surface charge that preserve their properties, including anthocyanins in the flavylium cation form, under conditions that mimic the gastrointestinal tract pH changes. SC-Nanophytosomes, 3 µM in phospholipid, and 2.5 mg/L of EAE-extract, delivered by drinking water to a rotenone-induced PD rat model, showed significant positive outcomes on disabling motor symptoms associated with the disease. Ex vivo assays were performed with two brain portions, one comprising the basal ganglia and cerebellum (BG-Cereb) and the other with the cerebral cortex (C-Cortex) regions. Results showed that rotenone-induced neurodegeneration increases the α-synuclein levels in the BG-Cereb portion and compromises mitochondrial respiratory chain functionality in both brain portions, well-evidenced by a 50% decrease in the respiratory control rate and up to 40% in complex I activity. Rotenone-induced PD phenotype is also associated with changes in superoxide dismutase and catalase activities that are dependent on the brain portion. Treatment with SC-Nanophytosomes reverted the α-synuclein levels and antioxidant enzymes activity to the values detected in control animals. Moreover, it mitigated mitochondrial dysfunction, with positive outcomes on the respiratory control rate, the activity of individual respiratory complexes, and the fatty acid profile of the membrane phospholipids. Therefore, SC-Nanophytosomes are a promising tool to support mitochondria-targeted therapy for neurodegenerative diseases.

Parabens enhance the calcium-dependent testicular mitochondrial permeability transition: Their relevance on the reproductive capacity in male animals.

Parabens, alkyl ester derivatives from p-hydroxybenzoic acid, are extensively used as antimicrobial preservatives. Nonetheless, due to its widespread and massive employment, several studies highlighted the association between parabens and alterations in the reproductive system. This study aimed to relate the adverse effect of the most commonly used parabens in testis mitochondria with male fertility. From all the parabens used, propyl and butyl were the ones that most negatively decreased the respiratory control ratio. In the case of butyl, inhibitions of 20% and 60% were observed, respectively, at the lowest and highest concentration, when compared to the control group. The membrane potential was only significantly affected by propyl (14%) and butyl (31%), and at a concentration of 250 µM. Succinate dehydrogenase, cytochrome c oxidase, and ATPase activities showed a nonsignificant decrease. Cytochrome c reductase, on the other hand, showed statistically significant inhibitions for both propyl (56%) and butylparaben (55%). The susceptibility to the mitochondrial permeability transition pore (MPTP) opening was increased by all parabens, although this increase was markedly significant for propyl and butyl. These results show that the susceptibility of mitochondria to parabens is dependent on the alkyl chain length and parabens hydrophobicity, and the main mitochondrial target is Complex II-III and MPTP. Hence, this study demonstrates the contribution of parabens exposition to the inhibition of testis mitochondrial function and their putative noxious effect on the male reproductive system.

Sperm DNA damage and seminal antioxidant activity in subfertile men.

Supraphysiological ROS levels can lead to apoptosis, lipid peroxidation, and DNA and protein damage. This pilot study aimed to investigate the sperm oxidative damage in subfertile men, to describe the relationship between the antioxidant system and ROS. Sixty-four semen samples were categorised according to the evaluated routine parameters (WHO, WHO laboratory manual for the examination and processing of human semen, 2010). Results were cross-referenced with the DNA damage [Comet (n = 53) and TUNEL (n = 49) assays], antioxidant enzyme activity [SOD (n = 51), CAT (n = 48) and GST (n = 48)], and content of total thiols (n = 36), lipid hydroperoxides (n = 35) and MDA (n = 31). Compared to pathospermic samples, normozoospermic presented 40%-45% fewer spermatozoa with fragmented DNA, 19% fewer hydroperoxides, and slightly higher total thiols and MDA levels. Asthenozoospermic/asthenoteratozoospermic samples had the lowest GST activity. SOD and CAT showed a similar trend. Our results evidenced significant positive correlations between DNA damage and immotile spermatozoa; SOD and CAT, GST and total thiols; CAT and GST; total thiols and sperm concentration; and MDA levels and head/midpiece abnormalities and hydroperoxides. This work contributes to the existing body of knowledge by showing that the oxidative status correlates with the classic sperm analysis parameters. Oxidative stress and DNA damage evaluation might be a valuable diagnostic and prognostic tool in cases of idiopathic male subfertility.

Elucidating the mechanisms of action of parecoxib in the MG-63 osteosarcoma cell line.

Different types of tumors often present an overexpression of cyclooxygenase-2. The aim of this study was to evaluate the effects of parecoxib (NSAID, cyclooxygenase-2 selective inhibitor) in the behavior of the human osteosarcoma MG-63 cell line, concerning several biological features. Cells were exposed to several concentrations of parecoxib for 48 hours. Cell viability/proliferation, cyclooxygenase-2 expression, morphologic alterations, membrane integrity, cell cycle evaluation, cell death and genotoxicity were evaluated. When compared with untreated cells, parecoxib led to a marked decrease in cell viability/proliferation, in COX-2 expression and changes in cell morphology, in a concentration-dependent manner. Cell recuperation was observed after incubation with drug-free medium. Parecoxib exposure increased lactate dehydrogenase release, an arrest of the cell cycle at S-phase and G2/M-phase, as well as growth of the sub-G0/G1-fraction and increased DNA damage. Parecoxib led to a slight increase of necrosis regulated cell death in treated cells, and an increase of autophagic vacuoles, in a concentration-dependent manner. In this study, parecoxib showed antitumor effects in the MG-63 human osteosarcoma cells. The potential mechanism was inhibiting cell proliferation and promoting necrosis. These results further suggested that parecoxib might be a potential candidate for in-vivo studies.

The Cyclooxigenase-2 Inhibitor Parecoxib Prevents Epidermal Dysplasia in HPV16-Transgenic Mice: Efficacy and Safety Observations.

Carcinogenesis induced by high-risk human papillomavirus (HPV) involves inflammatory phenomena, partially mediated by cyclooxigenase-2. In pre-clinical models of HPV-induced cancer, cyclooxygenase-2 inhibitors have shown significant efficacy, but also considerable toxicity. This study addresses the chemopreventive effect and hepatic toxicity of a specific cyclooxigensase-2 inhibitor, parecoxib, in HPV16-transgenic mice. Forty-three 20 weeks-old female mice were divided into four groups: I (HPV16-/-, n = 10, parecoxib-treated); II (HPV16-/- n = 11, untreated); III (HPV16+/-, n = 11, parecoxib-treated) and IV (HPV16+/-, n = 11, untreated). Parecoxib (5.0 mg/kg once daily) or vehicle was administered intraperitoneally for 22 consecutive days. Skin lesions were classified histologically. Toxicological endpoints included genotoxic parameters, hepatic oxidative stress, transaminases and histology. Parecoxib completely prevented the onset of epidermal dysplasia in HPV16+/- treated animals (0% versus 64% in HPV16+/- untreated, p = 0.027). Parecoxib decreases lipid peroxidation (LPO) and superoxide dismutase (SOD) activity and increases the GSH:GSSG ratio in HPV16+/- treated animals meaning that oxidative stress is lower. Parecoxib increased genotoxic stress parameters in wild-type and HPV16-transgenic mice, but didn't modify histological or biochemical hepatic parameters. These results indicate that parecoxib has chemopreventive effects against HPV16-induced lesions while maintaining an acceptable toxicological profile in this model.

Biochemical and transcriptional analyses of cadmium-induced mitochondrial dysfunction and oxidative stress in human osteoblasts.

Cadmium (Cd) accumulation is known to occur predominantly in kidney and liver; however, low-level long-term exposure to Cd may also result in bone damage. Few studies have addressed Cd-induced toxicity in osteoblasts, particularly upon cell mitochondrial energy processing and putative associations with oxidative stress in bone. To assess the influence of Cd treatment on mitochondrial function and oxidative status in osteoblast cells, human MG-63 cells were treated with Cd (up to 65 µM) for 24 or 48 h. Intracellular reactive oxygen species (ROS), lipid and protein oxidation and antioxidant defense mechanisms such as total antioxidant activity (TAA) and gene expression of antioxidant enzymes were analyzed. In addition, Cd-induced effects on mitochondrial function were assessed by analyzing the activity of enzymes involved in mitochondrial respiration, membrane potential (ΔΨm), mitochondrial morphology and adenylate energy charge. Treatment with Cd increased oxidative stress, concomitantly with lipid and protein oxidation. Real-time polymerase chain reaction (qRT-PCR) analyses of antioxidant genes catalase (CAT), glutathione peroxidase 1 (GPX1), glutathione S-reductase (GSR), and superoxide dismutase (SOD1 and SOD2) exhibited a trend toward decrease in transcripts in Cd-stressed cells, particularly a downregulation of GSR. Longer treatment with Cd (48 h) resulted in energy charge states significantly below those commonly observed in living cells. Mitochondrial function was affected by ΔΨm reduction. Inhibition of mitochondrial respiratory chain enzymes and citrate synthase also occurred following Cd treatment. In conclusion, Cd induced mitochondrial dysfunction which appeared to be associated with oxidative stress in human osteoblasts.

Acute ketamine impairs mitochondrial function and promotes superoxide dismutase activity in the rat brain.

BACKGROUND: Ketamine is often associated with altered mitochondrial function and oxidative stress. Nevertheless, limited data are still available regarding the in vivo action of ketamine in mitochondrial bioenergetics and redox state. Accumulating evidence supports a role for nitric oxide (NO) as a possible modulator of ketamine's side effects. In the present study, we investigated the role of NO modulation on ketamine anesthesia at the level of brain mitochondrial function and redox status. METHODS: Adult male rats received a single dose of ketamine (50, 100, or 150 mg/kg IP) or a combination of ketamine and N-nitro-L-arginine (3 mg/kg IP). Animals were killed 6 hours after treatment. Brain and blood samples were collected for plasma NO determination and mitochondria isolation. Several variables of brain mitochondrial function were evaluated. RESULTS: Ketamine interfered with complex I function, revealing increased oxygen consumption in state 4, impaired oxidative phosphorylation efficiency of glutamate-malate substrate, and decreased NADH-ubiquinone oxidoreductase activity. In addition, mitochondrial NO synthase (mtNOS) activity and NO plasma levels were increased for the 50 and 100 mg/kg doses. Ketamine administration increased hydrogen peroxide generation and triggered superoxide dismutase activity. All these effects could totally or partially be prevented by mtNOS inhibition through N-nitro-L-arginine. CONCLUSIONS: Acute ketamine administration impaired the function of mitochondrial complex I leading to increased mtNOS activity, increased generation of hydrogen peroxide and NO, resulting in superoxide dismutase triggering, and improved antioxidant activity. The present findings clarify the role of NO modulation in ketamine anesthesia, providing new data on a relevant clinical mechanism.

Membrane lipid profile alterations are associated with the metabolic adaptation of the Caco-2 cells to aglycemic nutritional condition.

Cancer cells can adapt their metabolic activity under nutritional hostile conditions in order to ensure both bioenergetics and biosynthetic requirements to survive. In this study, the effect of glucose deprivation on Caco-2 cells bioenergetics activity and putative relationship with membrane lipid changes were investigated. Glucose deprivation induces a metabolic remodeling characterized at mitochondrial level by an increase of oxygen consumption, arising from an improvement of complex II and complex IV activities and an inhibition of complex I activity. This effect is accompanied by changes in cellular membrane phospholipid profile. Caco-2 cells grown under glucose deprivation show higher phosphatidylethanolamine content and decreased phosphatidic acid content. Considering fatty acid profile of all cell phospholipids, glucose deprivation induces a decrease of monounsaturated fatty acid (MUFA) and n-3 polyunsaturated fatty acids (PUFA) simultaneously with an increase of n-6 PUFA, with consequent drop of n-3/n-6 ratio. Additionally, glucose deprivation affects significantly the fatty acid profile of all individual phospholipid classes, reflected by an increase of peroxidability index in zwitterionic phospholipids and a decrease in all anionic phospholipids, including mitochondrial cardiolipin. These data indicate that Caco-2 cells metabolic remodeling induced by glucose deprivation actively involves membrane lipid changes associated with a specific bioenergetics profile which ensure cell survival.

Impact of ozone therapy on mouse liver mitochondrial function and antioxidant system.

Ozone therapy's efficacy might stem from the regulated and mild oxidative stress resulting from ozone's interactions with various biological elements. The present work aimed to characterize the hepatic mitochondrial response to ozone treatment and its relationship with the antioxidant system response. Two groups of mice were used: one control group and another injected intraperitoneally with an O3/O2 mixture (80 ml/kg) for 5 days. Mitochondrial respiration supported by different substrates was significantly inhibited, as well as complexes I and II/III, but not complex IV. The analysis of the electron transport chain complex activity showed significant inhibitions in complexes I and II/III but not in complex IV. These inhibitions can prevent mitochondrial reactive oxygen species (ROS) production. Additionally, there was a decline in glutathione content, unaccompanied by a rise in its oxidized form. The ozone-treated groups showed a significant increase in the activity of superoxide dismutase and glutathione peroxidase, while catalase and glutathione reductase experienced no significant alterations. Adenine nucleotides increased in the ozone group, but only the increase in adenosine diphosphate is significant, so the cell's energy charge is unaffected. This study shows that mitochondria may play a crucial role in ozone treatment. However, it also highlights the need for further studies to understand the molecular mechanism.

The Effect of Lemon Juice (Citrus limon L.) Treated with Melatonin on the Health Status and Treatment of K14HPV16 Mice.

Lemon is a fruit rich in antioxidant properties and has several health benefits, namely the reduction of skin edema and anticarcinogenic properties, which are due to its high content of bioactive compounds. Melatonin can improve and preserve the properties of lemon for longer and also has health benefits. The aim of this study was to evaluate the effects of oral administration of lemon juice after melatonin treatment on murinometric parameters of wild-type (WT) mice and transgenic mice carrying human papillomavirus (HPV). Two trials were performed for oral administration of the lemon extract compound: in drinking water and in diet. First of all, lemons were treated by immersion with melatonin at 10 mM. Then, lemons were squeezed, and the juice obtained was freeze-dried and stored to be subsequently added to drinking water or diet, according to the assay. Thus, mice were divided into eight groups in the drink assay (each with n = 5): group 1 (G1, WT, control), group 2 (G2, WT, 1 mL lemon), group 3 (G3, WT, 1.5 mL lemon), group 4 (G4, WT, 2 mL lemon), group 5 (G5, HPV16, control), group 6 (G6, HPV16, 1 mL lemon) group 7 (G6, HPV16, 1.5 mL lemon) and group 8 (G6, HPV16, 2 mL lemon). The diet assay was divided into four groups: group 1 (G1, WT, control), group 2 (G2, WT, 4 mL lemon), group 3 (G3, HPV16, control) and group 4 (G4, HPV16, 4 mL lemon). In the drink assay, the highest concentration of melatonin (308 ng/100 mL) was for groups 4 and 8, while in the food assay, there was only one concentration of melatonin (9.96 ng/g) for groups 2 and 4. Both trials lasted 30 days. During this time, body weight, food and water were recorded. Afterward, they were sacrificed, and samples were collected for different analyses. At the concentrations used, the lemon juice with melatonin had no adverse effects on the animals' health and showed a positive outcome in modifying weight gain and enhancing antioxidant activity in mice. Moreover, a reduction in the incidence of histological lesions was observed in treated animals. Further research is needed to better understand the effects of lemon extract on health and treatment outcomes in this animal model.

Rapeseed oil-rich diet alters hepatic mitochondrial membrane lipid composition and disrupts bioenergetics.

Diet is directly related with physiological alterations occurring at a cell and subcellular level. However, the role of diet manipulation on mitochondrial physiology is still largely unexplored. Aiming at correlating diet with alterations of mitochondrial membrane composition and bioenergetics, Wistar-Han male rats were fed for 11, 22 and 33 days with a rapeseed oil-based diet and mitochondrial bioenergetics, and membrane composition were compared at each time point with a standard diet group. Considerable differences were noticed in mitochondrial membrane lipid composition, namely in terms of fatty acyl chains and relative proportions of phospholipid classes, the modified diet inducing a decrease in the saturated to unsaturated molar ratio and an increase in the phosphatidylcholine to phosphatidylethanolamine molar ratio. Mass spectrometry lipid analysis showed significant differences in the major species of cardiolipin, with an apparent increased incorporation of oleic acid as a result of exposure to the modified diet. Rats fed the modified diet during 22 days showed decreased hepatic mitochondrial state 3 respiration and were more susceptible to Ca(2+)-induced transition pore opening. Rapeseed oil-enriched diet also appeared to promote a decrease in hydroperoxide production by the respiratory chain, although a simultaneous decrease in vitamin E content was detected. In conclusion, our data indicate that the rapeseed oil diet causes negative alterations on hepatic mitochondrial bioenergetics, which may result from membrane remodeling. Such alterations may have an impact not only on energy supply to the cell, but also on drug-induced hepatic mitochondrial liabilities.

Mitochondrial and liver oxidative stress alterations induced by N-butyl-N-(4-hydroxybutyl)nitrosamine: relevance for hepatotoxicity.

The most significant toxicological effect of nitrosamines like N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) is their carcinogenic activity, which may result from exposure to a single large dose or from chronic exposure to relatively small doses. However, its effects on mitochondrial liver bioenergetics were never investigated. Liver is the principal organ responsible for BBN metabolic activation, and mitochondria have a central function in cellular energy production, participating in multiple metabolic pathways. Therefore any negative effect on mitochondrial function may affect cell viability. In the present work, ICR male mice were given 0.05% of BBN in drinking water for a period of 12 weeks and were sacrificed one week later. Mitochondrial physiology was characterized in BBN- and control-treated mice. Transmembrane electric potential developed by mitochondria was significantly affected when pyruvate-malate was used, with an increase in state 4 respiration observed for pyruvate-malate (46%) and succinate (38%). A decrease in the contents of one subunit of mitochondrial complex I and in one subunit of mitochondrial complex IV was also observed. In addition, the activity of both complexes I and II was also decreased by BBN treatment. The treatment with BBN increases the susceptibility of liver mitochondria to the opening of the mitochondrial permeability transition pore. This susceptibility could be related with the increase in the production of H2 O2 by mitochondria and increased oxidative stress confirmed by augmented susceptibility to lipid peroxidation. These results lead to the conclusion that hepatic mitochondria are one primary target for BBN toxic action during liver metabolism.

Effects of chronic exposure of naturally weathered microplastics on oxidative stress level, behaviour, and mitochondrial function of adult zebrafish (Danio rerio).

Microplastics (MPs) are a big and growing environmental concern, with studies showing sublethal to acute biological impacts on typical aquatic organisms. However, little is known about the biological effects of naturally weathered MPs, particularly focusing on mitochondria dysfunction as the key trigger of the biological effects. Therefore, in this study, naturally weathered MPs were produced from day-to-day life products, characterized, and chronically exposed (21 days) to adult zebrafish at the concentration of 0.1 and 1 mg/L. Locomotion and unconditioned anxiety-like behaviour was assessed. Mitochondrial respiration, membrane potential, mitochondrial complex activity and oxidative-related parameters were evaluated in the brain and liver. The results revealed the weathered MPs as a copolymer of propylene and ethylene that induced anxiety-like behaviour. There was an increase in brain catalase activity while the brain lactate dehydrogenase activity was inhibited after exposure to 1 mg/L. Brain glutathione levels were increased while their ratio was not affected. Mitochondrial respiratory chain complex Ⅱ and IV were also significantly decreased in the brain, although not compromising mitochondrial function. On the other hand, exposure to 1 mg/L caused a deficiency in liver mitochondrial respiration and decreased mitochondrial membrane potential, which were associated with the mitochondrial respiratory chain inhibition. An increase in hepatic superoxide dismutase and catalase activity was noticed, supporting the occurrence of ROS-induced ROS release as the potential trigger for the mitochondrial dysfunction. Overall, these findings highlight the potential indirect and cumulative environmental effects these particles may pose to aquatic ecosystems.

Assessing micro and nanoplastics toxicity using rodent models: Investigating potential mitochondrial implications.

Mitochondria's role as a central hub in cellular metabolism and signaling cascades is well established in the scientific community, being a classic marker of organisms' response to toxicant exposure. Nonetheless, little is known concerning the effects of emerging contaminants, such as microplastics, on mitochondrial metabolism. Micro- and nanoplastics present one of the major problems faced by modern societies. What was once an environmental problem is now recognized as an one-health issue, but little is known concerning microplastic impact on human health. Indeed, only recently, human exposure to microplastics was acknowledged by the World Health Organization, resulting in a growing interest in this research topic. Nonetheless, the mechanisms behind micro- and nanoplastics toxicity are yet to be understood. Animal models, nowadays, are the most appropriate approach to uncovering this knowledge gap. In the present review article, we explore investigations from the last two years using rodent models and reach to find the molecular mechanism behind micro- and nanoplastics toxicity and if mitochondria can act as a target. Although no research article has addressed the effects of mitochondria yet, reports have highlighted molecular and biochemical alterations that could be linked to mitochondrial function. Furthermore, certain studies described the effects of disruptions in mitochondrial metabolism, such as oxidative stress. Micro- and nanoplastics may, directly and indirectly, affect this vital organelle. Investigations concerning this topic should be encouraged once they can bring us closer to understanding the mechanisms underlying these particles' harmful effects on human health.

Tacrine and its analogues impair mitochondrial function and bioenergetics: a lipidomic analysis in rat brain.

Tacrine is an acetylcholinesterase (AChE) inhibitor used as a cognitive enhancer in the treatment of Alzheimer's disease (AD). However, its low therapeutic efficiency and a high incidence of side effects have limited its clinical use. In this study, the molecular mechanisms underlying the impact on brain activity of tacrine and two novel tacrine analogues (T1, T2) were approached by focusing on three aspects: (i) their effects on brain cholinesterase activity; (ii) perturbations on electron transport chain enzymes activities of non-synaptic brain mitochondria; and (iii) the role of mitochondrial lipidome changes induced by these compounds on mitochondrial bioenergetics. Brain effects were evaluated 18 h after the administration of a single dose (75.6 µmol/kg) of tacrine or tacrine analogues. The three compounds promoted a significant reduction in brain AChE and butyrylcholinesterase (BuChE) activities. Additionally, tacrine was shown to be more efficient in brain AChE inhibition than T2 tacrine analogue and less active than T1 tacrine analogue, whereas BuChE inhibition followed the order: T1 > T2 > tacrine. The studies using non-synaptic brain mitochondria show that all the compounds studied disturbed brain mitochondrial bioenergetics mainly via the inhibition of complex I activity. Furthermore, the activity of complex IV is also affected by tacrine and T1 treatments while FoF(1) -ATPase is only affected by tacrine. Therefore, the compounds' toxicity as regards brain mitochondria, which follows the order: tacrine >> T1 > T2, does not correlate with their ability to inhibit brain cholinesterase enzymes. Lipidomics approaches show that phosphatidylethanolamine (PE) is the most abundant phospholipids (PL) class in non-synaptic brain mitochondria and cardiolipin (CL) present the greatest diversity of molecular species. Tacrine induced significant perturbations in the mitochondrial PL profile, which were detected by means of changes in the relative abundance of phosphatidylcholine (PC), PE, phosphatidylinositol (PI) and CL and by the presence of oxidized phosphatidylserines. Additionally, in both the T1 and T2 groups, the lipid content and molecular composition of brain mitochondria PL are perturbed to a lesser extent than in the tacrine group. Abnormalities in CL content and the amount of oxidized phosphatidylserines were associated with significant reductions in mitochondrial enzymes activities, mainly complex I. These results indicate that tacrine and its analogues impair mitochondrial function and bioenergetics, thus compromising the activity of brain cells.

Microcystin-LR and chemically degraded microcystin-LR electrochemical oxidation.

Microcystins (MCs) are cyclic hepatotoxic heptapeptides produced by certain strains of freshwater cyanobacteria toxic for humans and animals. The electrochemical behaviour of microcystin-LR (MC-LR) at a glassy carbon electrode (GCE) was investigated using cyclic voltammetry (CV), square wave voltammetry (SWV) and differential pulse voltammetry (DPV). The oxidation of MC-LR is a diffusion-controlled irreversible and pH-independent process that occurs with the transfer of only one electron and does not involve the formation of any electroactive oxidation product. Upon incubation in different pH electrolytes, homogeneous degradation of MC-LR in solution was electrochemically detected by the appearance of a new oxidation peak at a lower potential. The electrochemical behaviour of chemically degraded MC-LR is an irreversible, pH-dependent process, and involves the formation of two redox products that undergo reversible oxidation. The formation of degradation products of MC-LR was confirmed by HPLC with UV detection at room temperature. Experiments were also carried out in solutions containing constituent MC-LR amino acids, which enabled the understanding of the MC-LR electron transfer reaction and degradation. An oxidation mechanism for MC-LR is proposed.

Mitochondria research and neurodegenerative diseases: On the track to understanding the biological world of high complexity.

From the simple unicellular eukaryote to the highly complex multicellular organism like Human, mitochondrion emerges as a ubiquitous player to ensure the organism's functionality. It is popularly known as "the powerhouse of the cell" by its key role in ATP generation. However, our understanding of the physiological relevance of mitochondria is being challenged by data obtained in different fields. In this review, a short history of the mitochondria research field is presented, stressing the findings and questions that allowed the knowledge advances, and put mitochondrion as the main player of safeguarding organism life as well as a key to solve the puzzle of the neurodegenerative diseases.

Multicomponent exercise program effects on fitness and cognitive function of elderlies with mild cognitive impairment: Involvement of oxidative stress and BDNF.

Regular exercise has been shown to be one of the most important lifestyle influences on improving functional performance, and decreasing morbidity and all-cause mortality among older people. However, although there is some evidence on the effects of aerobic training on oxidative stress, there is little information regarding the effects of multicomponent exercise (dual-task training) and combination of exercise with cognitive stimulation on oxidative stress. In this context, the aim of this study was to verify the effects of a multicomponent exercise program on physical fitness and cognitive function in the elderly with mild cognitive impairment and determine the role of oxidative stress and brain-derived neurotrophic factor (BDNF). At baseline, 37 elderly nursing home residents with mild cognitive impairment were divided into two groups: the control group (CG, n = 12, 81.8 years) and the experimental group (EG, n = 25, 83.2 years). These elderlies followed multicomponent exercise training for 24 weeks, with two sessions per week and 45-50 min per session. The exercises included both aerobic and strength exercises, considering functional movements and light to moderate intensity. Cognitive stimulation comprehended exercises based on word games, puzzles, mathematical calculations, forward and backward counting, computer exercises, exergames, and games on a balanced platform. Physical assessments (weight, height, and body mass index), health and functional parameters (fitness tests: chair stand, arm curls, chair sit-and-reach, eight feet up-and-go, back scratch, 6-min walking, feet together, semi-tandem, and full tandem), lipid profile (total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides), measures of lipid peroxidation damage, thiobarbituric acid reactive substances (TBARS), total antioxidant capacity (TAC), and BDNF were measured in plasma, based on which analyses were performed before and after the 24 weeks of the multicomponent exercise intervention. The results showed an overall improvement in physical and functional performance. Regarding biochemical measures, multicomponent exercises lead to a significant decrease in oxidative damage. The results indicate that multicomponent exercise training induces benefits in functional capacity and reduces damage due to oxidative stress.