Effects of sulforaphane on brain mitochondria: mechanistic view and future directions.

The organosulfur compound sulforaphane (SFN; C6H11NOS2) is a potent cytoprotective agent promoting antioxidant, anti-inflammatory, antiglycative, and antimicrobial effects in in vitro and in vivo experimental models. Mitochondria are the major site of adenosine triphosphate (ATP) production due to the work of the oxidative phosphorylation (OXPHOS) system. They are also the main site of reactive oxygen species (ROS) production in nucleated human cells. Mitochondrial impairment is central in several human diseases, including neurodegeneration and metabolic disorders. In this paper, we describe and discuss the effects and mechanisms of action by which SFN modulates mitochondrial function and dynamics in mammalian cells. Mitochondria-related pro-apoptotic effects promoted by SFN in tumor cells are also discussed. SFN may be considered a cytoprotective agent, at least in part, because of the effects this organosulfur agent induces in mitochondria. Nonetheless, there are certain points that should be addressed in further experiments, indicated here as future directions, which may help researchers in this field of research.

Suicide and associated factors across life span / Suicídio e fatores associados ao longo da vida

ABSTRACT Objective To assess the epidemiological and toxicological profile of all suicide victims in 2017 in Rio Grande do Sul, Brazil. Methods The victims were classified by gender, age, parental absence, city, suicide form, death context, and toxicological results, using the police occurrences and the reports issued by the Instituto-Geral de Perícias do RS. Multiple correspondence analysis and the Cochran-Mantel-Haenszel X 2 test were used to evaluate associations between the parameters studied. Results There were 1,284 suicides (11.3 cases/100,000 inhabitants) in RS in 2017, 80% of which were men and 46% were young and old. Porto Alegre had the highest number of victims and the region of the Vale do Rio Pardo, the highest rate (20.8 cases/100,000 inhabitants). The hanging was the most used medium and the depression, the most mentioned context in the occurrences. The presence of ethanol was observed in 30% of the samples analyzed, with an adult male profile associated with the presence of other psychotropic substances, whose class was most frequently detected with anxiolytics. The nitrite was the most detected poison among the samples sent for this purpose. There was an association between parental absence and young people, between suicidal intoxication method and women and among young people and the presence of illicit compounds. Conclusion Mortality due to suicide continues to increase in RS, which, historically, has the highest Brazilian index. The information obtained in this study supports new research, promoting awareness raising, guidance to health services and the elaboration of more preventive public policies.

RESUMO Objetivo Determinar o perfil epidemiológico e toxicológico de todas as vítimas de suicídio no Rio Grande do Sul em 2017. Métodos As vítimas foram classificadas por gênero, idade, ausência parental, cidade, forma de suicídio, contexto do óbito e resultados toxicológicos, utilizando as ocorrências policiais e os laudos emitidos pelo Instituto-Geral de Perícias do RS. A análise de correspondência múltipla e o teste Cochran-Mantel-Haenszel X 2 foram utilizados para avaliar associações entre os parâmetros estudados. Resultados Foram registrados 1.284 suicídios (11,3 casos/100 mil habitantes) no RS em 2017, sendo 80% homens e 46% jovens e idosos. Porto Alegre apresentou o maior número de vítimas e a região do Vale do Rio Pardo, o maior índice (20,8 casos/100 mil habitantes). O enforcamento foi o meio mais empregado e a depressão, o contexto mais citado nas ocorrências. A presença de etanol foi observada em 30% das amostras analisadas, com perfil masculino adulto associado à presença de outros psicotrópicos, cuja classe mais frequentemente detectada foi a dos ansiolíticos. O nitrito foi o veneno mais detectado entre as amostras encaminhadas para essa finalidade. Houve associação entre a ausência parental e os jovens, entre o método suicida intoxicação e as mulheres e entre os jovens e a presença de compostos ilícitos. Conclusão A mortalidade por suicídio segue aumentando no RS, que, historicamente, apresenta o maior índice brasileiro. As informações obtidas neste trabalho servem de apoio a novas pesquisas, promovendo ações de conscientização, orientação aos serviços de saúde e na elaboração de mais políticas públicas preventivas.

Resveratrol and Brain Mitochondria: a Review.

Resveratrol (3,4',5-trihydroxystilbene; C14H12O3) is a polyphenolic phytoalexin found in grapes, berries, peanuts, and wines. Resveratrol has been viewed as an antioxidant, anti-inflammatory, anti-apoptotic, and anticancer agent. Moreover, it has been reported that resveratrol modulates mitochondrial function, redox biology, and dynamics in both in vitro and in vivo experimental models. Resveratrol also attenuates mitochondrial impairment induced by certain stressors. Resveratrol upregulates, for example, mitochondria-located antioxidant enzymes, decreasing the production of reactive species by these organelles. Resveratrol also triggers mitochondrial biogenesis, ameliorating the mitochondria-related bioenergetics status in mammalian cells. In the present work, we discuss about the effects of resveratrol on brain mitochondria. Brain cells (both neuronal and glial) are susceptible to mitochondrial dysfunction due to their high demand for adenosine triphosphate (ATP). Additionally, brain cells consume oxygen (O2) at very high rates, leading to a proportionally high mitochondrial production of reactive species. Therefore, strategies focusing on the maintenance of mitochondrial function in these cell types are of pharmacological interest in the case of neurodegenerative diseases, which involve mitochondrial impairment and increased generation of reactive species, leading to neuroinflammation and cell death. The mechanism by which resveratrol protects mitochondrial function and dynamics is not completely understood, and further research would be necessary in order to investigate exactly how resveratrol affects mitochondria-related parameters. Furthermore, it is particularly important because resveratrol is able to induce cytotoxicity depending on its dosage.

Curcumin, mitochondrial biogenesis, and mitophagy: Exploring recent data and indicating future needs.

Mitochondria are dynamic double-membrane bound organelles which have key roles in a variety of cellular functions such as energy producing, regulation of calcium flux, cellular stress responses including autophagy and apoptosis. A growing body of evidence indicates that mitochondrial dysfunction is the main culprit in a myriad of diseases such as neurodegenerative disease. This fact opens a new therapeutic window based on targeting mitochondrial dysfunction for treatment of these diseases. Recently an abundance of evidence shows the promising role of polyphenolic compounds on mitochondrial structure and function. Curcumin, a well-known polyphenolic compound, is an abundant component of turmeric. The promising roles of curcumin against different diseases are highly publicized. The aim of the present work is to critically review the scientific evidence to provide a clear view of how curcumin improves mitochondrial dynamics regarding mitochondrial biogenesis and mitophagy. We also present curcumin biosynthesis, source, bioavailability and metabolism in order to give an overview of this compound.

Cocaine and mitochondria-related signaling in the brain: A mechanistic view and future directions.

Cocaine is extensively used as a psychostimulant among subjects at different ages worldwide. Cocaine causes neuronal dysfunction and, consequently, negatively affects human behavior and decreases life quality severely. Cocaine acts through diverse mechanisms, including mitochondrial impairment and activation of cell signaling pathways associated to stress response. There is some controversy regarding the effect of cocaine in inducing cell death through apoptosis in different experimental models. The aim of the present work is to discuss data associated to the mitochondrial consequences of cocaine exposure of mammalian cells in several experimental models from in vitro to in vivo, including postmortem human tissue analyses. Furthermore, future directions are proposed in order to serve as a suggestive guide in relation to the next steps towards the complete elucidation of the mechanisms of toxicity elicited by cocaine upon mitochondria of neuronal cells.

Lipoteichoic acid from Staphylococcus aureus increases matrix metalloproteinase 9 expression in RAW 264.7 macrophages: modulation by A2A and A2B adenosine receptors.

Peptidoglycan (PEG) and lipoteichoic acid (LTA) are the main constituents of Gram-positive bacteria cell wall and are described to modulate immune functions. Increased levels of matrix metalloproteinases (MMPs) were described in endotoxemia, suggesting that they participate to tecidual damage, multiple organs failure and vascular disfunction. Staphylococcus aureus PEG is described to increase MMPs 2 and 9 levels in plasma from rat and MMP 9 secretion by human neutrophils, however, the effect of LTA on MMPs is unknown. In this work, was evaluated the modulation of MMPs 2 and 9 expression and secretion in RAW 264.7 macrophages by LTA from S. aureus. The role of A2A and A2B adenosine receptors was also investigated. LTA increased MMP 9 expression and secretion at 12h of treatment. The modulation of MMP 9 secretion was dose dependent, with maximal effect above 1microg/ml. The inhibitor of mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway (U0126, 10microM) prevented LTA stimulation of MMP 9 secretion; however, the inhibitors of p38 (SB203580, 10microM) and Jun N-terminal kinase (JNK; SP600125, 10microM) presented any effect. A2A and A2B adenosine receptors pharmacological blockade or gene knockdown resulted in exacerbated MMP 9 secretion, while an adenosine receptors agonist inhibited LTA-stimulated MMP 9 secretion. These results suggest that LTA increased MMP 9 secretion in macrophages could be involved in complications associated to S. aureus infections. Moreover, LTA modulation of MMP 9 is dependent on MEK/ERK pathway and is regulated by A2A and A2B adenosine receptors.

High glucose increases RAW 264.7 macrophages activation by lipoteichoic acid from Staphylococcus aureus.

BACKGROUND: Type 2 diabetes mellitus is associated with an increased risk of cardiovascular diseases and accelerated atherosclerosis, which has been associated to hyperglycemia and chronic inflammation. Activated macrophages are described to participate in atherosclerosis due to foam cell formation and pro-inflammatory mediators production. Bacterial infections are described to accelerate atherosclerosis, moreover, gram-positive and negative bacterial DNA was described in atherosclerotic plaques. METHODS: We studied the glucose modulation of RAW 264.7 macrophages activation by the gram-positive bacterial antigen lipoteichoic acid (LTA), evaluating nitrite production, tumor necrosis factor alpha secretion and matrix metalloproteinase 9 activity. RESULTS: High glucose increased macrophages activation by LTA, evidenced by exacerbated nitric oxide and tumor necrosis factor alpha production, as well matrix metalloproteinase 9 secretion. CONCLUSIONS: These effects could contribute to atherosclerotic risk parameters, like atherome plaque instability, and participate in chronic inflammation present in type 2 diabetes.

Activity and expression of ecto-5'-nucleotidase/CD73 are increased during phenotype conversion of a hepatic stellate cell line.

Hepatic stellate cells (HSC) play a crucial role in the development of liver fibrosis and are important targets in liver disease therapy. Adenosine acts as an extracellular signaling molecule in various tissues and in liver this nucleoside exerts protective effects. Ecto-5'-nucleotidase/CD73 is a marker for the plasma membrane and is considered to be a key enzyme in the generation of adenosine in the extracellular medium, by transforming AMP into adenosine. In addition, adenosine production from AMP is also catalyzed by alkaline phosphatase. We compared the extracellular metabolism of AMP and transcriptional levels of the ecto-5'-nucleotidase/CD73 and tissue non-specific alkaline phosphatase (TNALP) in activated and quiescent HSC of the mouse hepatic stellate cell line GRX. This cell line expresses a myofibroblast phenotype in basal medium and both retinol and indomethacin treatment induced a phenotypic change of GRX cells to quiescent HSC. Ecto-5'-nucleotidase activity and its mRNA expression were found to be higher in quiescent HSC than in activated HSC. During phenotype conversion, mediated by retinol, the AMP decay was accelerated with adenosine accumulation in extracellular medium, likely due to the decrease in adenosine deaminase activity also observed in quiescent HSC. The treatment with retinol also involves transcriptional activation of TNALP. Taken together, these data suggest that ecto-5'-nucleotidase-dependent adenosine generation may play a role in the regulation of quiescent HSC functions.

Extracellular inosine participates in tumor necrosis factor-alpha induced nitric oxide production in cultured Sertoli cells.

Recent reports have described purinergic modulation of tumor necrosis factor-alpha (TNF-alpha) signaling in neutrophils and astrocytes. In Sertoli cells, both TNF-R1 and TNF-R2 TNF-alpha receptors are present and this cytokine modulates many functions of these cells related to the maintenance of spermatogenesis. Sertoli cells express distinct purinoreceptors and previous work has shown that these cells secrete extracellular nucleotides and their metabolites. In this work, we studied the possible role of extracellular purines in TNF-alpha signaling in cultured Sertoli cells. This cytokine increased inosine concentration from 30 min to 6 h, with no effect at 24 h. Both TNF-alpha and inosine increased nitrite accumulation and nitric oxide synthase activity. Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase inhibitor, abolished the TNF-alpha induced inosine increase, nitrite accumulation and nitric oxide synthase activity. These results suggest that extracellular inosine acts as intermediary in TNF-alpha stimulated nitric oxide production in cultured Sertoli cells.

Extracellular inosine is modulated by H2O2 and protects sertoli cells against lipoperoxidation and cellular injury.

Extracellular purines are involved in the regulation of a wide range of physiological processes, including cytoprotection, ischemic preconditioning, and cell death. These actions are usually mediated via triggering of membrane purinergic receptors, which may activate antioxidant enzymes, conferring cytoprotection. Recently, it was demonstrated that the oxidative stress induced by cisplatin up-regulated A1 receptor expression in rat testes, suggesting an involvement of purinergic signaling in the response of testicular cells to oxidant injury. In this article, we report the effect of hydrogen peroxide on purinergic agonist release by cultured Sertoli cells. Extracellular inosine levels are strongly increased in the presence of H2O2, suggesting an involvement of this nucleoside on Sertoli cells response to oxidant treatment. Inosine was observed to decrease H2O2-induced lipoperoxidaton and cellular injury, and it also preserved cellular ATP content during H2O2 exposure. These effects were abolished in the presence of nucleoside uptake inhibitors, indicating that nucleoside internalisation is essential for its action in preventing cell damage.