Antineoplastic copper coordinated complexes (Casiopeinas) uncouple oxidative phosphorylation and induce mitochondrial permeability transition in cardiac mitochondria and cardiomyocytes.

Copper-based drugs, Casiopeinas (Cas), exhibit antiproliferative and antineoplastic activities in vitro and in vivo, respectively. Unfortunately, the clinical use of these novel chemotherapeutics could be limited by the development of dose-dependent cardiotoxicity. In addition, the molecular mechanisms underlying Cas cardiotoxicity and anticancer activity are not completely understood. Here, we explore the potential impact of Cas on the cardiac mitochondria energetics as the molecular mechanisms underlying Cas-induced cardiotoxicity. To explore the properties on mitochondrial metabolism, we determined Cas effects on respiration, membrane potential, membrane permeability, and redox state in isolated cardiac mitochondria. The effect of Cas on the mitochondrial membrane potential (Δψm) was also evaluated in isolated cardiomyocytes by confocal microscopy and flow cytometry. Cas IIIEa, IIgly, and IIIia predominately inhibited maximal NADH- and succinate-linked mitochondrial respiration, increased the state-4 respiration rate and reduced membrane potential, suggesting that Cas also act as mitochondrial uncouplers. Interestingly, cyclosporine A inhibited Cas-induced mitochondrial depolarization, suggesting the involvement of mitochondrial permeability transition pore (mPTP). Similarly to isolated mitochondria, in isolated cardiomyocytes, Cas treatment decreased the Δψm and cyclosporine A treatment prevented mitochondrial depolarization. The production of H2O2 increased in Cas-treated mitochondria, which might also increase the oxidation of mitochondrial proteins such as adenine nucleotide translocase. In accordance, an antioxidant scavenger (Tiron) significantly diminished Cas IIIia mitochondrial depolarization. Cas induces a prominent loss of membrane potential, associated with alterations in redox state, which increases mPTP opening, potentially due to thiol-dependent modifications of the pore, suggesting that direct or indirect inhibition of mPTP opening might reduce Cas-induced cardiotoxicity.

Corrigendum to "Sphingolipids as Mediators in the Crosstalk between Microbiota and Intestinal Cells: Implications for Inflammatory Bowel Disease".

[This corrects the article DOI: 10.1155/2016/9890141.].

Oxidative stress in cardiomyocytes contributes to decreased SERCA2a activity in rats with metabolic syndrome.

Ca(+) mishandling due to impaired activity of cardiac sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) has been associated with the development of left ventricular diastolic dysfunction in insulin-resistant cardiomyopathy. However, the molecular causes underlying SERCA2a alterations induced by insulin resistance and related metabolic disorders, such as metabolic syndrome (MetS), are not completely understood. In this study, we used a sucrose-fed rat model of MetS to test the hypothesis that decreased SERCA2a activity is mediated by elevated oxidative stress produced in the MetS heart. Production of ROS and cytosolic Ca(2+) concentration were recorded in left ventricular myocytes using confocal imaging. The level of SERCA2a oxidation was determined in left ventricular homogenates by biotinylated iodoacetamide labeling. Compared with control rats, sucrose-fed rats exhibited several characteristics of MetS, including central obesity, insulin resistance, hyperinsulinemia, and hypertriglyceridemia. Moreover, relative to myocytes from control rats, myocytes from MetS rats exhibited elevated basal production of ROS accompanied by slowed cytosolic Ca(2+) removal, reflected by prolonged Ca(2+) transients. The slowed cytosolic Ca(2+) removal was associated with a significant decrease in SERCA2a-mediated Ca(2+) reuptake and increased SERCA2a oxidation. Importantly, myocytes from MetS rats treated with the antioxidant N-acetylcysteine showed normal ROS levels and SERCA2a-mediated Ca(2+) reuptake as well as accelerated cytosolic Ca(2+) removal. These data suggest that elevated oxidative stress may induce oxidative modifications on SERCA2a leading to abnormal function of this protein in the MetS heart.

Oxidative stress in early metabolic syndrome impairs cardiac RyR2 and SERCA2a activity and modifies the interplay of these proteins during Ca2+ waves.

We investigated how oxidative stress (OS) alters Ca2+ handling in ventricular myocytes in early metabolic syndrome (MetS) in sucrose-fed rats. The effects of N-acetyl cysteine (NAC) or dl-Dithiothreitol (DTT) on systolic Ca2+ transients (SCaTs), diastolic Ca2+ sparks (CaS) and Ca2+ waves (CaW), recorded by confocal techniques, and L-type Ca2+ current (ICa), assessed by whole-cell patch clamp, were evaluated in MetS and Control cells. MetS myocytes exhibited decreased SCaTs and CaS frequency but unaffected CaW propagation. In Control cells, NAC/DTT reduced RyR2/SERCA2a activity blunting SCaTs, CaS frequency and CaW propagation, suggesting that basal ROS optimised Ca2+ signalling by maintaining RyR2/SERCA2a function and that these proteins facilitate CaW propagation. Conversely, NAC/DTT in MetS recovered RyR2/SERCA2a function, improving SCaTs and CaS frequency, but unexpectedly decreasing CaW propagation. We hypothesised that OS decreases RyR2/SERCA2a activity at early MetS, and while decreased SERCA2a favours CaW propagation, diminished RyR2 restrains it.

Increased oxidative stress contributes to enhance brain amyloidogenesis and blunts energy metabolism in sucrose-fed rat: effect of AMPK activation.

Metabolic disturbances are linked to neurodegenerative diseases such as Alzheimer disease (AD). However, the cellular mechanisms underlying this connection are unclear. We evaluated the role of oxidative stress (OS), during early metabolic syndrome (MetS), on amyloidogenic processes in a MetS rat model induced by sucrose. MetS caused OS damage as indicated by serum and hypothalamus lipid peroxidation and elevated serum catalase activity. Tissue catalase and superoxide dismutase activity were unchanged by MetS, but gene expression of nuclear factor erythroid-derived 2-like 2 (NFE2L2), which up-regulates expression of antioxidant enzymes, was higher. Expression of amyloid-ß cleaving enzyme 1 (BACE-1) and amyloid precursor protein (APP), key proteins in the amyloidogenesis pathway, were slightly increased by sucrose-intake in the hippocampus and hypothalamus. Activation and expression of protein kinase B (PKB) and AMP-dependent protein kinase (AMPK), pivotal proteins in metabolism and energy signaling, were similarly affected in the hippocampus and hypothalamus of MetS rats. Brain creatine kinase activity decreased in brain tissues from rats with MetS, mainly due to irreversible oxidation. Chronic metformin administration partially reversed oxidative damage in sucrose-fed animals, together with increased AMPK activation; probably by modulating BACE-1 and NFE2L2. AMPK activation may be considered as a preventive therapy for early MetS and associated neurodegenerative diseases.

Biochemical and nutritional overview of diet-induced metabolic syndrome models in rats: what is the best choice?

Metabolic syndrome (MS) is a condition that includes obesity, insulin resistance, dyslipidemias among other, abnormalities that favors type 2 Diabetes Mellitus (T2DM) and cardiovascular diseases development. Three main diet-induced metabolic syndrome models in rats exist: High carbohydrate diet (HCHD), high fat diet (HFD), and high carbohydrate-high fat diet (HCHHFD). We analyzed data from at least 35 articles per diet, from different research groups, to determine their effect on the development of the MS, aimed to aid researchers in choosing the model that better suits their research question; and also the best parameter that defines obesity, as there is no consensus to determine this condition in rats. For the HCHD we found a mild effect on body weight gain and fasting blood glucose levels (FBG), but significant increases in triglycerides, fasting insulin, insulin resistance and visceral fat accumulation. HFD had the greater increase in the parameters previously mentioned, followed by HCHHFD, which had a modest effect on FBG levels. Therefore, to study early stages of MS a HCHD is recommended, while HFD and HCHHFD better reproduce more severe stages of MS. We recommend the assessment of visceral fat accumulation as a good estimate for obesity in the rat.

Castration modifies aortic vasoreactivity and serum fatty acids in a sucrose-fed rat model of metabolic syndrome.

Levels of testosterone and estradiol influence the incidence of cardiovascular diseases: generally, estrogens in females are protective before menopause; coronaropathies, hypertension, and dyslipidemias in normal men are more frequent at comparable ages. We investigated the modulation by castration of in vitro vasoreactivity, serum lipid content, and systolic blood pressure (SBP) in rats with sucrose-induced metabolic syndrome. The main characteristics of the rat model are: hypertriglyceridemia, moderately high blood pressure, intra-abdominal accumulation of adipose tissue, hyperinsulinemia, nephropathy, increased oxidative stress, and altered vasoreactivity. Male weanling rats received 30% sucrose solution for 16 weeks (metabolic syndrome; MS), controls (C) had plain water; both had commercial rodent chow. They were subdivided into five groups with two subgroups each: Group 1, intact C and MS rats, Groups 2-5, C and MS rats castrated for periods of 16, 12, 8, and 4 weeks. At the end of the study period, systolic blood pressure was measured, and blood and aortas were obtained for fatty acid determination and vasoreactivity assays, respectively. After 16 weeks' sucrose treatment MS aortas showed hypercontractility and decreased vasodilation. Palmitic and palmitoleic acids were increased in MS versus C. Arachidonic acid levels in MS were lower than in intact or castrated C. Long-term castration of 16 weeks normalized the levels of palmitic and oleic acids. With the shorter periods of castration, contractility increased and relaxation decreased in C and MS, but it was more significant in C. Regarding fatty acid composition, long-term castration increased polyunsaturated (arachidonic and eicosapentaenoic) fatty acids. The shorter periods did not modify the fatty acid profile in either C or MS. Metabolic syndrome altered SBP, aortic reactivity, and levels of fatty acids; castration of long duration normalized them in some cases.

Species-specific inhibition of Giardia lamblia triosephosphate isomerase by localized perturbation of the homodimer.

Giardia lamblia depends on glycolysis to obtain ATP, highlighting the suitability of glycolytic enzymes as targets for drug design. We studied triosephosphate isomerase from G. lamblia (GlTIM) as a potential species-specific drug target. Cysteine-reactive agents were used as probes, in order to test those regions near to cysteine residues as targets to perturb enzyme structure and activity. Methyl methanethiosulfonate (MMTS) derivatized three of the five Cys per subunit of dimeric GlTIM and induced 50% of inactivation. The 2-carboxyethyl methanethiosulfonate (MTSCE) modified four Cys and induced 97% of inactivation. Inactivation by MMTS or MTSCE did not affect secondary structure, nor induce dimer dissociation; however, Cys modification decreased thermal stability of enzyme. Inactivation and dissociation of the dimer to stable monomers were reached when four Cys were derivatized by 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB). The effects of DTNB were completely abolished when GlTIM was first treated with MMTS. The effect of thiol reagents on human TIM was also assayed; it is 180-fold less sensitive than GlTIM. Collectively, the data illustrate GlTIM as a good target for drug design.

Functional and metabolic implications of biotin deficiency for the rat heart.

The tricarboxylic acid (TCA) cycle is the main ATP provider for the heart. TCA carbons must be replenished by anaplerosis for normal cardiac function. Biotin is cofactor of the anaplerotic enzymes pyruvate and propionyl-CoA carboxylases. Here, we found that in biotin deficient rats, both carboxylases decreased 90% in adipose tissue, jejunum and spleen, but in heart they conserved about 60% residual activity. We then investigated if under biotin deficiency (BtDEF), the heart is able to maintain its function in vivo and in isolated conditions, and during ischemia and reperfusion, where metabolism drastically shifts from oxidative to mainly glycolytic. Neither glucose nor octanoate oxidation were severely affected in BtDEF hearts, as assessed by mechanical performance, oxygen uptake or high-energy metabolite content; however, myocardial hexokinase activity and lactate concentration were reduced in deficient hearts. When challenged by ischemia and reperfusion injury, BtDEF hearts did not suffer more damage than the controls, although they lowered significantly their performance, when changed to ischemic conditions, which may have clinical implications. Post-ischemic increase in ADP/ATP ratio was similar in both groups, but during reperfusion there was higher rhythm perturbation in BtDEF hearts. By being relatively insensitive to biotin deficiency, cardiac tissue seems to be able to replenish TCA cycle intermediates and to maintain ATP synthesis.

Ex Vivo Cardiotoxicity of Antineoplastic Casiopeinas Is Mediated through Energetic Dysfunction and Triggered Mitochondrial-Dependent Apoptosis.

Casiopeinas are a group of copper-based antineoplastic molecules designed as a less toxic and more therapeutic alternative to cisplatin or Doxorubicin; however, there is scarce evidence about their toxic effects on the whole heart and cardiomyocytes. Given this, rat hearts were perfused with Casiopeinas or Doxorubicin and the effects on mechanical performance, energetics, and mitochondrial function were measured. As well, the effects of Casiopeinas-triggered cell death were explored in isolated cardiomyocytes. Casiopeinas III-Ea, II-gly, and III-ia induced a progressive and sustained inhibition of heart contractile function that was dose- and time-dependent with an IC50 of 1.3 ± 0.2, 5.5 ± 0.5, and 10 ± 0.7 µM, correspondingly. Myocardial oxygen consumption was not modified at their respective IC50, although ATP levels were significantly reduced, indicating energy impairment. Isolated mitochondria from Casiopeinas-treated hearts showed a significant loss of membrane potential and reduction of mitochondrial Ca2+ retention capacity. Interestingly, Cyclosporine A inhibited Casiopeinas-induced mitochondrial Ca2+ release, which suggests the involvement of the mitochondrial permeability transition pore opening. In addition, Casiopeinas reduced the viability of cardiomyocytes and stimulated the activation of caspases 3, 7, and 9, demonstrating a cell death mitochondrial-dependent mechanism. Finally, the early perfusion of Cyclosporine A in isolated hearts decreased Casiopeinas-induced dysfunction with reduction of their toxic effect. Our results suggest that heart cardiotoxicity of Casiopeinas is similar to that of Doxorubicin, involving heart mitochondrial dysfunction, loss of membrane potential, changes in energetic metabolites, and apoptosis triggered by mitochondrial permeability.

[PPARs, metabolic syndrome and cardiac diseases]. / PPARs, síndrome metabólico y enfermedad cardíaca.

The nuclear receptor PPARs (peroxisomal proliferators-activated receptors) are transcription factors activated by natural and synthetic ligands. Three different isoforms of PPARs have been described, PPARalpha, PPARbeta/ delta, and PPARgamma. PPARs isoforms are tissue-dependent expressed and they regulate the gene expression of proteins involved in glucose and lipid metabolism. Selective pharmacological activation of these isoforms has revealed their role in cellular physiology. Nowadays, two kinds of PPARs agonists are currently used in the clinical practice, the fibrate hypolipidemic drugs, used in the treatment of dyslipidemia, are synthetic ligands for PPARalpha, whereas thiazolidinediones or glitazones have PPARgamma selectivity and are used as hypoglycemic agents. The main cellular effect of PPAR activation lies on fatty acid oxidation and mobilization (PPARalpha) as well as they act as insulin sensitizers on peripheral tissues (PPARgamma). In addition to these beneficial effects of PPARs, it has also been demonstrated that PPARs activation can prevent cardiac dysfunction in diabetic patients as well as the anti-inflammatory processes developed in many diseases. Recent development of PPARbeta/delta and hybrid PPARs alpha and gamma agonists, and their clinical trials are giving promising outcomes in the therapeutics of metabolic syndrome, diabetes and cardiac diseases.

The mediating role of work-family conflict in the relationship between organizational justice and work-related stress / Rol mediador del conflicto trabajo-familia en la relación entre justicia organizacional y estrés laboral

Abstract Although the effects of overall organizational justice on perceptions of work-related stress have been demonstrated in previous studies, the mechanisms underlying this relationship are not explicit. Current research suggests that supervisors who are perceived as fair enhance employees' ability to balance their work and family roles, positively impacting their stress levels. The aim of this research is to examine the mediating role of work-family conflict in the relationship between perceptions of overall organizational justice and work-related stress in a Latin-American work context; also analyze gender differences in work-family/work-family conflict. 129 workers belonging to a Chilean public institution participated and answered a self-report questionnaire. Analyses were done using bivariate correlations of Pearson, Tau-b of Kendall, Student t-test and structural equation modeling. The results showed the existence of a significant negative correlation between perceptions of overall organizational justice and work-related stress. Furthermore, this relationship was partially mediated by work-family conflict, which means, perceptions of organizational justice were directly and indirectly associated with work-related stress, through work-family conflict. With respect to the gender variable and the work-family, no significant differences were found. This study contributes empirical evidence regarding the importance of perceptions of overall organizational justice and the work-family conflict on work-related stress, and the results obtained guide the diagnosis and the design of more specific models of prevention and intervention from the perspective of occupational health psychology.

Resumen Si bien los efectos de las percepciones de justicia organizacional global sobre las percepciones de estrés laboral han sido demostrados en estudios previos, los mecanismos que subyacen a esta relación no resultan explícitos. La investigación actual plantea que las jefaturas percibidas como más justas potencian la capacidad del trabajador para conciliar sus roles laborales y familiares, impactando positivamente sus niveles de estrés. El objetivo de este estudio es analizar, en un contexto laboral latinoamericano, el rol mediador del conflicto trabajo-familia en la relación entre las percepciones de justicia organizacional global y estrés laboral; y analizar diferencias entre hombres y mujeres respecto al conflicto trabajo-familia. Participaron 129 trabajadores pertenecientes a una institución pública chilena, quienes contestaron un cuestionario de autoreporte. Se efectuaron correlaciones bivariadas de Pearson, Tau-b de Kendall, prueba t de Student y modelamiento de ecuaciones estructurales. Los resultados mostraron la existencia de una correlación negativa y significativa entre las percepciones de justicia organizacional global y el estrés laboral. Además, esta relación estuvo mediada parcialmente por el conflicto trabajo-familia, es decir, las percepciones de justicia organizacional se asociaron de manera directa e indirecta al estrés laboral, a través del conflicto trabajo-familia. Respecto de la variable género y el conflict trabajo-familia, no se encontraron diferencias significativas. Este estudio aporta evidencia empírica sobre la importancia de las percepciones de justicia organizacional global, y sus resultados orientan el diagnóstico y la elaboración de modelos de prevención e intervención más específicos desde el campo de la psicología de la salud ocupacional.

Metabolic Syndrome as a Risk Factor for Alzheimer's Disease: Is Aß a Crucial Factor in Both Pathologies?

SIGNIFICANCE: Recently, chronic degenerative diseases have become one of the main health problems worldwide. That is the case of Alzheimer's disease (AD) and metabolic syndrome (MetS), whose expression can be influenced by different risk factors. Recent Advances: In recent decades, it has been widely described that MetS increases the risk of cognitive impairment and dementia. MetS pathogenesis involves several vascular risk factors such as diabetes, dyslipidemia, hypertension, and insulin resistance (I/R). CRITICAL ISSUES: Reported evidence shows that vascular risk factors are associated with AD, particularly in the development of protein aggregation, inflammation, oxidative stress, neuronal dysfunction, and disturbances in signaling pathways, with insulin receptor signaling being a common alteration between MetS and AD. FUTURE DIRECTIONS: Insulin signaling has been involved in tau phosphorylation and amyloid ß (Aß) metabolism. However, it has also been demonstrated that Aß oligomers can bind to insulin receptors, triggering their internalization, decreasing neuron responsiveness to insulin, and promoting insulin I/R. Thus, it could be argued that Aß could be a convergent factor in the development of both pathologies. Antioxid. Redox Signal. 26, 542-560.

The MXL-3/SBP-1 Axis Is Responsible for Glucose-Dependent Fat Accumulation in C. elegans.

Chronic exposure to elevated glucose levels leads to fatty acid accumulation, which promotes the development of metabolic diseases such as obesity and type 2 diabetes. MXL-3 is a conserved transcriptional factor that modulates the inhibition of lipolysis in Caenorhabditis elegans. However, the role of MXL-3 in lipid metabolism during nutrient excess remains unknown. We hypothesized that inhibition of MXL-3 prevents glucose-dependent fat accumulation. Nematodes from wild-type N2, MXL-3::GFP and sbp-1 or mxl-3 null strains were grown on standard, high glucose or high glucose plus metformin plates for 24 h. Using laser-scanning confocal microscopy, we monitored the glucose-induced activation of MXL-3 labeled with GFP (MXL-3::GFP). Lipid levels were determined by Oil Red O (ORO) staining and gas chromatography/mass spectrometry, and gene expression was assessed by qRT-PCR. We found that high glucose activated MXL-3 by increasing its rate of nuclear entry, which in turn increased lipid levels via sterol regulatory element-binding protein (SBP-1). This activated critical genes that synthesize long chain unsaturated fatty acids (MUFAs and PUFAs) and repress lipolytic genes. Interestingly, the anti-diabetic drug metformin inhibited MXL-3 activation and subsequently prevented glucose-dependent fat accumulation. These findings highlight the importance of the MXL-3/SBP-1 axis in the regulation of lipid metabolism during nutritional excess and provide new insight into the mechanism by which metformin prevents lipid accumulation. This study also suggests that inhibition of MXL-3 may serve as a potential target for the treatment of chronic metabolic diseases, including obesity, type 2 diabetes, and cardiovascular disease.

Proinflammatory Cytokines Are Soluble Mediators Linked with Ventricular Arrhythmias and Contractile Dysfunction in a Rat Model of Metabolic Syndrome.

Metabolic syndrome (MS) increases cardiovascular risk and is associated with cardiac dysfunction and arrhythmias, although the precise mechanisms are still under study. Chronic inflammation in MS has emerged as a possible cause of adverse cardiac events. Male Wistar rats fed with 30% sucrose in drinking water and standard chow for 25-27 weeks were compared to a control group. The MS group showed increased weight, visceral fat, blood pressure, and serum triglycerides. The most important increases in serum cytokines included IL-1ß (7-fold), TNF-α (84%), IL-6 (41%), and leptin (2-fold), the latter also showing increased gene expression in heart tissue (35-fold). Heart function ex vivo in MS group showed a decreased mechanical performance response to isoproterenol challenge (ISO). Importantly, MS hearts under ISO showed nearly twofold the incidence of ventricular fibrillation. Healthy rat cardiomyocytes exposed to MS group serum displayed impaired contractile function and Ca2+ handling during ISO treatment, showing slightly decreased cell shortening and Ca2+ transient amplitude (23%), slower cytosolic calcium removal (17%), and more frequent spontaneous Ca2+ release events (7.5-fold). As spontaneous Ca2+ releases provide a substrate for ventricular arrhythmias, our study highlights the possible role of serum proinflammatory mediators in the development of arrhythmic events during MS.

Structural and functional changes in heart mitochondria from sucrose-fed hypertriglyceridemic rats.

In the heart of sugar-induced hypertriglyceridemic (HTG) rats, cardiac performance is impaired with glucose as fuel, but not with fatty acids. Accordingly, the glycolytic flux and the transfer of energy diminish in the HTG heart, in comparison to control heart. To further explore the biochemical nature of such alteration in the HTG heart, the components of the non-glycolytic energy systems involved were evaluated. Total creatine kinase (CK) activity in the myocardial tissue was depressed by 30% in the HTG heart whereas the activity of the mitochondrial CK (mitCK) isoenzyme fraction that is functionally associated with oxidative phosphorylation decreased in isolated HTG heart mitochondria by 45%. Adenylate kinase (AK) was 20% lower in the HTG heart. In contrast, respiratory rates with 2-oxoglutarate (2-OG) and pyruvate/malate (pyr) were significantly higher in HTG heart mitochondria than in control mitochondria. 2-OG dehydrogenase activity was also higher in HTG mitochondria. Respiration with succinate was similar in both groups. Content of cytochromes b, c + c1 and a + a3, and cytochrome c oxidase activity, were also similar in the two kinds of mitochondria. A larger content of saturated and monounsaturated fatty acids was found in the HTG mitochondrial membranes with no changes in phospholipids composition or cholesterol content. Mitochondrial membranes from HTG hearts were more rigid, which correlated with the generation of higher membrane potentials. As the mitochondrial function was preserved or even enhanced in the HTG heart, these results indicated that deficiency in energy transfer was associated with impairment in mitCK and AK. This situation brought about uncoupling between the site of ATP production and the site of ATP consumption (contractile machinery), in spite of compensatory increase in mitochondrial oxidative capacity and membrane potential generation.

AMP-Activated Protein Kinase Regulates Oxidative Metabolism in Caenorhabditis elegans through the NHR-49 and MDT-15 Transcriptional Regulators.

Cellular energy regulation relies on complex signaling pathways that respond to fuel availability and metabolic demands. Dysregulation of these networks is implicated in the development of human metabolic diseases such as obesity and metabolic syndrome. In Caenorhabditis elegans the AMP-activated protein kinase, AAK, has been associated with longevity and stress resistance; nevertheless its precise role in energy metabolism remains elusive. In the present study, we find an evolutionary conserved role of AAK in oxidative metabolism. Similar to mammals, AAK is activated by AICAR and metformin and leads to increased glycolytic and oxidative metabolic fluxes evidenced by an increase in lactate levels and mitochondrial oxygen consumption and a decrease in total fatty acids and lipid storage, whereas augmented glucose availability has the opposite effects. We found that these changes were largely dependent on the catalytic subunit AAK-2, since the aak-2 null strain lost the observed metabolic actions. Further results demonstrate that the effects due to AAK activation are associated to SBP-1 and NHR-49 transcriptional factors and MDT-15 transcriptional co-activator, suggesting a regulatory pathway that controls oxidative metabolism. Our findings establish C. elegans as a tractable model system to dissect the relationship between distinct molecules that play a critical role in the regulation of energy metabolism in human metabolic diseases.

Heart metabolic disturbances in cardiovascular diseases.

Myocardial function depends on adenosine triphosphate (ATP) supplied by oxidation of several substrates. In the adult heart, this energy is obtained primarily from fatty acid oxidation through oxidative phosphorylation. However, the energy source may change depending on several factors such as substrate availability, energy demands, oxygen supply, and metabolic condition of the individual. Surprisingly, the role of energy metabolism in development of cardiac diseases has not been extensively studied. For instance, alterations in glucose oxidation and transport developed in diabetic heart may compromise myocardial performance under conditions in which ATP provided by glycolysis is relevant, such as in ischemia and reperfusion. In some cardiac diseases such as ischemic cardiomyopathy, heart failure, hypertrophy, and dilated cardiomyopathy, ATP generation is diminished by derangement of fatty acid delivery to mitochondria and by alteration of certain key enzymes of energy metabolism. Shortage of some co-factors such as L-carnitine and creatine also leads to energy depletion. Creatine kinase system and other mitochondrial enzymes are also affected. Initial attempts to modulate cardiac energy metabolism by use of drugs or supplements as a therapeutic approach to heart disease are described.

Oxidative stress and metabolic syndrome: cause or consequence of Alzheimer's disease?

Alzheimer's disease (AD) is a major neurodegenerative disease affecting the elderly. Clinically, it is characterized by a progressive loss of memory and cognitive function. Neuropathologically, it is characterized by the presence of extracellular ß-amyloid (Aß) deposited as neuritic plaques (NP) and neurofibrillary tangles (NFT) made of abnormal and hyperphosphorylated tau protein. These lesions are capable of generating the neuronal damage that leads to cell death and cognitive failure through the generation of reactive oxygen species (ROS). Evidence indicates the critical role of Aß metabolism in prompting the oxidative stress observed in AD patients. However, it has also been proposed that oxidative damage precedes the onset of clinical and pathological AD symptoms, including amyloid-ß deposition, neurofibrillary tangle formation, vascular malfunction, metabolic syndrome, and cognitive decline. This paper provides a brief description of the three main proteins associated with the development of the disease (Aß, tau, and ApoE) and describes their role in the generation of oxidative stress. Finally, we describe the mitochondrial alterations that are generated by Aß and examine the relationship of vascular damage which is a potential prognostic tool of metabolic syndrome. In addition, new therapeutic approaches targeting ROS sources and metabolic support were reported.