Methionine and/or Methionine Sulfoxide Alter Ectoenzymes Activities in Lymphocytes and Inflammatory Parameters in Serum from Young Rats: Acute and Chronic Effects.

In this study we investigated the effect of acute and chronic treatment with Met and/or methionine sulfoxide (MetO) on ectonucleotidases and cholinesterases activities from lymphocytes and purine derivatives compounds, C-protein reactive, interleukin-10, interleukin-6, and tumor necrosis factor-α levels in serum of young rats. Adenosine triphosphate hydrolysis was decreased in lymphocytes 1 h after treatment by MetO and Met + MetO. However, adenosine triphosphate and adenosine diphosphate hydrolysis in lymphocytes was increased in the groups MetO and Met + MetO and adenosine deaminase activity was increased in MetO 3 h after the treatment. Acetylcholinesterase activity was increased in lymphocytes after 3 h and 21 days of treatment by MetO and Met + MetO, while serum butyrycholinesterase activity was decreased after 1 h and 21 days of treatment in the same groups. In chronic treatment, interleukin-6 and tumor necrosis factor-α level were increased, while that interleukin-10 level was decreased by Met, MetO, and Met + MetO when compared to control group. C-protein reactive level was increased by MetO and Met + MetO. Adenosine triphosphate and adenosine monophosphate levels were reduced in all amino acids treated groups, while adenosine diphosphate and hypoxanthine were enhanced by MetO and Met + MetO. Adenosine and xanthine were reduced in the MetO group, whereas inosine levels were decreased in the MetO and Met + MetO groups. These findings help to understand the inflammatory alterations observed in hypermethioninemia.

Acute administration of methionine and/or methionine sulfoxide impairs redox status and induces apoptosis in rat cerebral cortex.

High plasma levels of methionine (Met) and its metabolites such as methionine sulfoxide (MetO) may occur in several genetic abnormalities. Patients with hypermethioninemia can present neurological dysfunction; however, the neurotoxicity mechanisms induced by these amino acids remain unknown. The aim of the present work was to study the effects of Met and/or MetO on oxidative stress, genotoxicity, cytotoxicity and to evaluate whether the cell death mechanism is mediated by apoptosis in the cerebral cortex of young rats. Forty-eight Wistar rats were divided into groups: saline, Met 0.4 g/Kg, MetO 0.1 g/Kg and Met 0.4 g/Kg + MetO 0.1 g/Kg, and were euthanized 1 and 3 h after subcutaneous injection. Results showed that TBARS levels were enhanced by MetO and Met+MetO 1 h and 3 h after treatment. ROS was increased at 3 h by Met, MetO and Met+MetO. SOD activity was increased in the Met group, while CAT was reduced in all experimental groups 1 h and 3 h after treatment. GPx activity was enhanced 1 h after treatment by Met, MetO and Met+MetO, however it was reduced in the same experimental groups 3 h after administration of amino acids. Caspase-3, caspase-9 and DNA damage was increased and cell viability was reduced by Met, MetO and Met+MetO at 3 h. Also, Met, MetO and Met+MetO, after 3 h, enhanced early and late apoptosis cells. Mitochondrial electrochemical potential was decreased by MetO and Met+MetO 1 h and 3 h after treatment. These findings help understand the mechanisms involved in neurotoxicity induced by hypermethioninemia.

Neuroprotective Effects of Açaí (Euterpe oleracea Mart.) against Rotenone In Vitro Exposure.

Neuropsychiatric diseases, such as bipolar disorder (BD) and schizophrenia (SCZ), have a very complex pathophysiology. Several current studies describe an association between psychiatric illness and mitochondrial dysfunction and consequent cellular modifications, including lipid, protein, and DNA damage, caused by cellular oxidative stress. Euterpe oleracea (açaí) is a powerful antioxidant fruit. Açaí is an Amazonian palm fruit primarily found in the lowlands of the Amazonian rainforest, particularly in the floodplains of the Amazon River. Given this proposed association, this study analyzed the potential in vitro neuropharmacological effect of Euterpe oleracea (açaí) extract in the modulation of mitochondrial function and oxidative metabolism. SH-SY5Y cells were treated with rotenone to induce mitochondrial complex I dysfunction and before and after we exposed the cells to açaí extract at 5 µg/mL. Treated and untreated cells were then analyzed by spectrophotometric, fluorescent, immunological, and molecular assays. The results showed that açaí extract can potentially increase protein amount and enzyme activity of mitochondrial complex I, mainly through NDUFS7 and NDUFS8 overexpression. Açaí extract was also able to decrease cell reactive oxygen species levels and lipid peroxidation. We thus suggest açaí as a potential candidate for drug development and a possible alternative BD therapy.

Upstream Pathways Controlling Mitochondrial Function in Major Psychosis: A Focus on Bipolar Disorder.

Mitochondrial dysfunction is commonly observed in bipolar disorder (BD) and schizophrenia (SCZ) and may be a central feature of psychosis. These illnesses are complex and heterogeneous, which is reflected by the complexity of the processes regulating mitochondrial function. Mitochondria are typically associated with energy production; however, dysfunction of mitochondria affects not only energy production but also vital cellular processes, including the formation of reactive oxygen species, cell cycle and survival, intracellular Ca(2+) homeostasis, and neurotransmission. In this review, we characterize the upstream components controlling mitochondrial function, including 1) mutations in nuclear and mitochondrial DNA, 2) mitochondrial dynamics, and 3) intracellular Ca(2+) homeostasis. Characterizing and understanding the upstream factors that regulate mitochondrial function is essential to understand progression of these illnesses and develop biomarkers and therapeutics.

Evaluation of extracellular adenine nucleotides hydrolysis in platelets and biomarkers of oxidative stress in Down syndrome individuals.

PURPOSE: Down syndrome (DS) is caused by the triplication of chromosome 21. Studies have demonstrated platelets abnormalities and oxidative stress in DS subjects. The enzymes NTPDase, 5'-nucleotidase and adenosine deaminase (ADA) represent an important therapeutic target since they interfere in the extracellular nucleotide pool altering platelet functions. In this study, we evaluated the ectonucleotidases activities and oxidative stress parameters in samples of DS and healthy individuals. METHODS AND RESULTS: The population consisted of 28 subjects with DS and 28 healthy subjects as a control group. Blood was obtained from each subject and used for platelet and serum preparation. NTPDase activity using ATP as substrate was increased in platelets of DS patients in relation to the control group; however, no alterations were observed in the ADP hydrolysis. A decrease in the 5'-nucleotidase activity and an increase in the ADA activity was observed in platelet of DS subjects when compared to healthy individuals (P<0.05). The lipid peroxidation and total thiol content was decreased in serum of DS individuals. Furthermore, superoxide dismutase and catalase activities were increased in whole blood of this group (P<0.05). CONCLUSION: Alterations in the ectonucleotidase activities in platelets as well as changes in the oxidative stress parameters may contribute to the clinical features of DS.

Methionine and methionine sulfoxide alter parameters of oxidative stress in the liver of young rats: in vitro and in vivo studies.

It has been shown that elevation of plasma methionine (Met) and its metabolites may occur in several genetic abnormalities. In this study we investigated the in vitro and in vivo effects of the Met and methionine sulfoxide (MetO) on oxidative stress parameters in the liver of rats. For in vitro studies, liver homogenates were incubated with Met, MetO, and Mix (Met + MetO). For in vivo studies, the animals were divided into groups: saline, Met 0.4 g/kg, MetO 0.1 g/kg, and Met 0.4 g/kg + MetO 0.1 g/kg. The animals were euthanized 1 and 3 h after injection. In vitro results showed that Met 1 and 2 mM and Mix increased catalase (CAT) activity. Superoxide dismutase (SOD) was enhanced by Met 1 and 2 mM, MetO 0.5 mM, and Mix. Dichlorofluorescein oxidation was increased by Met 1 mM and Mix. In vivo results showed that Met, MetO, and Mix decreased TBARS levels at 1 h. Total thiol content decreased 1 h after and increased 3 h after MetO and Met plus MetO administrations. Carbonyl content was enhanced by Met and was reduced by MetO 1 h after administration. Met, MetO and Met plus MetO decreased CAT activity 1 and 3 h after administration. Furthermore, only MetO increased SOD activity. In addition, Met, MetO, and Mix decreased dichlorofluorescein oxidation at 1 and 3 h. Our data indicate that Met/MetO in vivo and in vitro modify liver homeostasis by altering the redox cellular state. However, the hepatic changes caused by these compounds suggest a short-time adaptation of this tissue.