Impact of carvedilol on the mitochondrial damage induced by hypoxanthine and xantine oxidase: what role in myocardial ischemia and reperfusion?

OBJECTIVES: The cardioprotective effects of carvedilol (CV) may be explained in part by interactions with heart mitochondria. The objective of this work was to study the protection afforded by CV against oxidative stress induced in isolated heart mitochondria by hypoxanthine and xanthine oxidase (HX/XO), a well-known source of reactive oxygen species (ROS) in the cardiovascular system. METHODS: Mitochondria were isolated from Wistar rat hearts (n = 8) and incubated with HX/XO in the presence and in the absence of calcium. Several methods were used to assess the protection afforded by CV: evaluation of mitochondrial volume changes (by measuring changes in the optical density of the mitochondrial suspension), calcium uptake and release (with a fluorescent probe, Calcium Green 5-N) and mitochondrial respiration (with a Clark-type oxygen electrode). RESULTS: CV decreased mitochondrial damage associated with ROS production by HX and XO, as verified by the reduction of mitochondrial swelling and increase in mitochondrial calcium uptake. In the presence of HX and XO, CV also ameliorated mitochondrial respiration in the active phosphorylation state and prevented decrease in the respiratory control ratio (p < 0.05) and in mitochondrial phosphorylative efficiency (p < 0.001). CONCLUSIONS: The data indicate that CV partly protected heart mitochondria from oxidative damage induced by HX and XO, which may be useful during myocardial ischemia and reperfusion. It is also suggested that mitochondria may be a priority target for the protective action of some compounds

Advantages in the use of carvedilol versus propranolol for the protection of cardiac mitochondrial function

BACKGROUND: Carvedilol is a neurohormonal antagonist of multiple action which is used in clinical practice for the treatment of congestive heart failure, mild to moderate hypertension and myocardial infarction. Previous results from our group have demonstrated that one of the main targets for the protective effect of carvedilol is the cardiac mitochondrial network. In-this work, we compare the effect of carvedilol with propranolol in different models of mitochondrial dysfunction and in the generation of transmembrane electric potential (EP). We further tested if carvedilol was able to inhibit the mitochondrial permeability transition (MPT) induced by doxorubicin and calcium-dependent cytochrome c release, a phenomenon frequently associated with apoptotic cell death. METHODS: Cardiac mitochondria were isolated by differential centrifugation. Oxygen consumption and mitochondrial EP were determined using an oxygen electrode and a tetraphenylphosphonium-sensitive electrode, respectively. Changes in mitochondrial volume and the release of cytochrome c were measured with spectrophotometric techniques. RESULTS: Propranolol, compared with carvedilol, had only a marginal effect, not only in protection against MPT induction, but also against oxygen consumption linked to the oxidation of external NADH, a process that is considered by several authors as key in the cardiotoxicity of doxorubicin. Regarding EP generation, propranolol had no effect, in contrast to carvedilol, which was confirmed to act as a protonophore. For the first time we also show that carvedilol inhibits the MPT induced by doxorubicin and calcium-dependent cytochrome c release. CONCLUSIONS: With this work, we further support the notion that carvedilol is effective in several models of mitochondrial dysfunction, particularly those involving oxidative stress. The results demonstrate that for some pathological conditions, carvedilol and propranolol have different mechanisms of action at the sub-cellular level, as propranolol seems to lack effectiveness in the protection of cardiac mitochondria

Histological changes and impairment of liver mitochondrial bioenergetics after long-term treatment with alpha-naphthyl-isothiocyanate (ANIT)

This study was designed to evaluate the effects of long-term treatment with alpha-naphthyl-isothiocyanate (ANIT) on liver histology and at the mitochondrial bioenergetic level. Since, ANIT has been used as a cholestatic agent and it has been pointed out that an impairment of mitochondrial function is a cause of hepatocyte dysfunction leading to cholestatic liver injury, serum markers of liver injury were measured and liver sections were analyzed in ANIT-treated rats (i.p. 80 mg/kg/week x 16 weeks). Mitochondrial parameters such as transmembrane potential, respiration, calcium capacity, alterations in permeability transition susceptibility and ATPase activity were monitored. Histologically, the most important features were the marked ductular proliferation, proliferation of mast cells and the presence of iron deposits in ANIT-treated liver. Mitochondria isolated from ANIT-treated rats showed no alterations in state 4 respiration, respiratory control ratio and ADP/O ratio, while state 3 respiration was significantly decreased. No changes were observed on transmembrane potential, but the repolarization rate was decreased in treated rats. Consistently with these data, there was a significant decrease in the ATPase activity of treated mitochondria. Associated with these parameters, mitochondria from treated animals exhibited increased susceptibility to mitochondrial permeability transition pore opening (lower calcium capacity). Since, human cholestatic liver disease progress slowly overtime, these data provide further insight into the role of mitochondrial dysfunction in the process

Gene polymorphisms of superoxide dismutases and catalase in diabetes mellitus

<p>Abstract</p> <p>Background</p> <p>Reactive oxygen species generated by hyperglycaemia modify structure and function of lipids, proteins and other molecules taking part in chronic vascular changes in diabetes mellitus (DM). Low activity of scavenger enzymes has been observed in patients with DM. Protective role of scavenger enzymes may be deteriorated by oxidative stress. This study was undertaken to investigate the association between gene polymorphisms of selected antioxidant enzymes and vascular complications of DM.</p> <p>Results</p> <p>Significant differences in allele and genotype distribution among T1DM, T2DM and control persons were found in SOD1 and SOD2 genes but not in CAT gene (p < 0,01). Serum SOD activity was significantly decreased in T1DM and T2DM subjects compared to the control subjects (p < 0,05). SOD1 and SOD2 polymorphisms may affect SOD activity. Serum SOD activity was higher in CC than in TT genotype of SOD2 gene (p < 0,05) and higher in AA than in CC genotype of SOD1 gene (p < 0,05). Better diabetes control was found in patients with CC than with TT genotype of SOD2 gene. Significantly different allele and genotype frequencies of SOD2 gene polymorphism were found among diabetic patients with macroangiopathy and those without it. No difference was associated with microangiopathy in all studied genes.</p> <p>Conclusion</p> <p>The results of our study demonstrate that oxidative stress in DM can be accelerated not only due to increased production of ROS caused by hyperglycaemia but also by reduced ability of antioxidant defense system caused at least partly by SNPs of some scavenger enzymes.</p

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Molecular Basis for Vulnerability to Mitochondrial and Oxidative Stress in a Neuroendocrine CRI-G1 Cell Line

Many age-associated disorders (including diabetes, cancer, and neurodegenerative diseases) are linked to mitochondrial dysfunction, which leads to impaired cellular bioenergetics and increased oxidative stress. However, it is not known what genetic and molecular pathways underlie differential vulnerability to mitochondrial dysfunction observed among different cell types.Starting with an insulinoma cell line as a model for a neuronal/endocrine cell type, we isolated a novel subclonal line (named CRI-G1-RS) that was more susceptible to cell death induced by mitochondrial respiratory chain inhibitors than the parental CRI-G1 line (renamed CRI-G1-RR for clarity). Compared to parental RR cells, RS cells were also more vulnerable to direct oxidative stress, but equally vulnerable to mitochondrial uncoupling and less vulnerable to protein kinase inhibition-induced apoptosis. Thus, differential vulnerability to mitochondrial toxins between these two cell types likely reflects differences in their ability to handle metabolically generated reactive oxygen species rather than differences in ATP production/utilization or in downstream apoptotic machinery. Genome-wide gene expression analysis and follow-up biochemical studies revealed that, in this experimental system, increased vulnerability to mitochondrial and oxidative stress was associated with (1) inhibition of ARE/Nrf2/Keap1 antioxidant pathway; (2) decreased expression of antioxidant and phase I/II conjugation enzymes, most of which are Nrf2 transcriptional targets; (3) increased expression of molecular chaperones, many of which are also considered Nrf2 transcriptional targets; (4) increased expression of β cell-specific genes and transcription factors that specify/maintain β cell fate; and (5) reconstitution of glucose-stimulated insulin secretion.The molecular profile presented here will enable identification of individual genes or gene clusters that shape vulnerability to mitochondrial dysfunction and thus represent potential therapeutic targets for diabetes and neurodegenerative diseases. In addition, the newly identified CRI-G1-RS cell line represents a new experimental model for investigating how endogenous antioxidants affect glucose sensing and insulin release by pancreatic β cells

TRY plant trait database - enhanced coverage and open access

Plant traits—the morphological, anatomical, physiological, biochemical and phenological characteristics of plants—determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits—almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives