Potential therapeutic use of the ketogenic diet in autism spectrum disorders.

The ketogenic diet (KGD) has been recognized as an effective treatment for individuals with glucose transporter 1 (GLUT1) and pyruvate dehydrogenase (PDH) deficiencies as well as with epilepsy. More recently, its use has been advocated in a number of neurological disorders prompting a newfound interest in its possible therapeutic use in autism spectrum disorders (ASD). One study and one case report indicated that children with ASD treated with a KGD showed decreased seizure frequencies and exhibited behavioral improvements (i.e., improved learning abilities and social skills). The KGD could benefit individuals with ASD affected with epileptic episodes as well as those with either PDH or mild respiratory chain (RC) complex deficiencies. Given that the mechanism of action of the KGD is not fully understood, caution should be exercised in ASD cases lacking a careful biochemical and metabolic characterization to avoid deleterious side effects or refractory outcomes

Plasma Biomarkers for Monitoring Brain Pathophysiology in FMR1 Premutation Carriers.

Premutation carriers have a 55-200 CGG expansion in the fragile X mental retardation 1 (FMR1) gene. Currently, 1.5 million individuals are affected in the United States, and carriers are at risk of developing the late-onset neurodegenerative disorder Fragile X-associated tremor ataxia syndrome (FXTAS). Limited efforts have been made to develop new methods for improved early patient monitoring, treatment response, and disease progression. To this end, plasma metabolomic phenotyping was obtained for 23 premutation carriers and 16 age- and sex-matched controls. Three biomarkers, phenylethylamine normalized by either aconitate or isocitrate and oleamide normalized by isocitrate, exhibited excellent model performance. The lower phenylethylamine and oleamide plasma levels in carriers may indicate, respectively, incipient nigrostriatal degeneration and higher incidence of substance abuse, anxiety and sleep disturbances. Higher levels of citrate, isocitrate, aconitate, and lactate may reflect deficits in both bioenergetics and neurotransmitter metabolism (Glu, GABA). This study lays important groundwork by defining the potential utility of plasma metabolic profiling to monitor brain pathophysiology in carriers before and during the progression of FXTAS, treatment efficacy and evaluation of side effects

Mitochondrial NAD+-dependent malic enzyme from Anopheles stephensi: a possible novel target for malaria mosquito control

<p>Abstract</p> <p>Background</p> <p><it>Anopheles stephensi </it>mitochondrial malic enzyme (ME) emerged as having a relevant role in the provision of pyruvate for the Krebs' cycle because inhibition of this enzyme results in the complete abrogation of oxygen uptake by mitochondria. Therefore, the identification of ME in mitochondria from immortalized <it>A. stephensi </it>(ASE) cells and the investigation of the stereoselectivity of malate analogues are relevant in understanding the physiological role of ME in cells of this important malaria parasite vector and its potential as a possible novel target for insecticide development.</p> <p>Methods</p> <p>To characterize the mitochondrial ME from immortalized ASE cells (Mos. 43; ASE), mass spectrometry analyses of trypsin fragments of ME, genomic sequence analysis and biochemical assays were performed to identify the enzyme and evaluate its activity in terms of cofactor dependency and inhibitor preference.</p> <p>Results</p> <p>The encoding gene sequence and primary sequences of several peptides from mitochondrial ME were found to be highly homologous to the mitochondrial ME from <it>Anopheles gambiae </it>(98%) and 59% homologous to the mitochondrial NADP⁺-dependent ME isoform from <it>Homo sapiens</it>. Measurements of ME activity in mosquito mitochondria isolated from ASE cells showed that (<it>i</it>) <it>V_max</it>with NAD⁺was 3-fold higher than that with NADP⁺, (<it>ii</it>) addition of Mg²⁺or Mn²⁺increased the <it>V_max</it>by 9- to 21-fold, with Mn²⁺2.3-fold more effective than Mg²⁺, (<it>iii</it>) succinate and fumarate increased the activity by 2- and 5-fold, respectively, at sub-saturating concentrations of malate, (<it>iv</it>) among the analogs of L-malate tested as inhibitors of the NAD⁺-dependent ME catalyzed reaction, small (2- to 3-carbons) organic diacids carrying a 2-hydroxyl/keto group behaved as the most potent inhibitors of ME activity (e.g., oxaloacetate, tartronic acid and oxalate).</p> <p>Conclusions</p> <p>The biochemical characterization of <it>Anopheles stephensi </it>ME is of critical relevance given its important role in bioenergetics, suggesting that it is a suitable target for insecticide development.</p

Hemin rescues adrenodoxin, heme a and cytochrome oxidase activity in frataxin-deficient oligodendroglioma cells

AbstractMutations in the frataxin gene cause neurodegeneration and demyelination in Friedreich's ataxia. We showed earlier that frataxin deficiency causes primary iron–sulfur cluster defects, and later causes defects in heme and cytochrome c hemoprotein levels. Iron–sulfur (Fe/S) clusters are required in two enzymes of heme biosynthesis in humans i.e. in ferrochelatase and adrenodoxin. However, decreases in ferrochelatase activity have not been observed in frataxin-deficient HeLa cells or patient lymphoblasts. We knocked down frataxin in oligodendroglioma cells using siRNA, which produced significant defects in the activity of the Fe/S cluster enzymes adrenodoxin and aconitase, the adrenodoxin product heme a, and cytochrome oxidase, for which heme a serves as a prosthetic group. Exogenous hemin produced a significant rescue of adrenodoxin, aconitase, heme a levels and cytochrome oxidase activity. Thus hemin rescues iron–sulfur cluster defects that are the result of frataxin-deficiency, perhaps as a consequence of increasing the pool of bioavailable iron, and thus should be more fully tested for beneficial effects in Friedreich's ataxia models

Premutation in the Fragile X Mental Retardation 1 (FMR1) Gene Affects Maternal Zn-milk and Perinatal Brain Bioenergetics and Scaffolding.

Fragile X premutation alleles have 55-200 CGG repeats in the 5' UTR of the FMR1 gene. Altered zinc (Zn) homeostasis has been reported in fibroblasts from &gt;60 years old premutation carriers, in which Zn supplementation significantly restored Zn-dependent mitochondrial protein import/processing and function. Given that mitochondria play a critical role in synaptic transmission, brain function, and cognition, we tested FMRP protein expression, brain bioenergetics, and expression of the Zn-dependent synaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (Shank3) in a knock-in (KI) premutation mouse model with 180 CGG repeats. Mitochondrial outcomes correlated with FMRP protein expression (but not FMR1 gene expression) in KI mice and human fibroblasts from carriers of the pre- and full-mutation. Significant deficits in brain bioenergetics, Zn levels, and Shank3 protein expression were observed in the Zn-rich regions KI hippocampus and cerebellum at PND21, with some of these effects lasting into adulthood (PND210). A strong genotype × age interaction was observed for most of the outcomes tested in hippocampus and cerebellum, whereas in cortex, age played a major role. Given that the most significant effects were observed at the end of the lactation period, we hypothesized that KI milk might have a role at compounding the deleterious effects on the FMR1 genetic background. A higher gene expression of ZnT4 and ZnT6, Zn transporters abundant in brain and lactating mammary glands, was observed in the latter tissue of KI dams. A cross-fostering experiment allowed improving cortex bioenergetics in KI pups nursing on WT milk. Conversely, WT pups nursing on KI milk showed deficits in hippocampus and cerebellum bioenergetics. A highly significant milk type × genotype interaction was observed for all three-brain regions, being cortex the most influenced. Finally, lower milk-Zn levels were recorded in milk from lactating women carrying the premutation as well as other Zn-related outcomes (Zn-dependent alkaline phosphatase activity and lactose biosynthesis-whose limiting step is the Zn-dependent β-1,4-galactosyltransferase). In premutation carriers, altered Zn homeostasis, brain bioenergetics and Shank3 levels could be compounded by Zn-deficient milk, increasing the risk of developing emotional and neurological/cognitive problems and/or FXTAS later in life

The iron roofs in Palermo’s Liberty

[SPA] La arquitectura del hierro se difunde en Europa en el siglo XIX, en coincidencia con el progreso de la siderurgia y el desarrollo de la extraordinaria estación del Art Nouveau, Movimiento que busca en la evolución del mundo moderno, del desarrollo industrial, del progreso de la tecnología, en las nuevas instancias sociales y culturales, una “forma” apropiada, satisfactoria de las nuevas instancias de representatividad. En esta atmósfera de renovación, la moderna tecnología asume un rol prioritario y el hierro se presta bien a adaptarse a las nuevas exigencias que se inspiran en la naturaleza y sus formas orgánicas. Hoy muchas manufacturas de hierro han desaparecido, han sido destruídas o demolidas, u otras se encuentran en un estado de total abandono y degradación. La presente investigación es el resultado de un estudio conducido por el Departamento de Arquitectura de la Universidad de Palermo, disertando sobre esas obras de la arquitectura de hierro realizadas en Palermo a caballo entre los dos siglos, con particular referencia a las cubiertas, que han sufrido en el curso de los años la acción del tiempo, pero sobre todo las consecuencias de la incuria de quien no reconoce estas obras testimonio histórico, artístico y cultural de la extraordinaria, aunque breve, estación del Art Nouveau en Sicilia. [ENG] The iron architecture spreads in Europe in the nineteenth century, coinciding with the advancement of the steel industry and the development of the extraordinary Art Nouveau period, a movement that analyses the evolution of the modern world, the industrial development, the advances in technology, the new social and cultural needs, to find a new suitable form to meet the new demands of representativeness. In this atmosphere of urban renewal, modern technology plays a primary role, and iron is well-suited to adapt to the new demands of taste that draw inspiration from nature and its organic forms. Many of the iron works of the period have disappeared, destroyed or demolished and others are in a total status of abandon and decay. The contribution is the result of a study carried out at the Department of Architecture of the University of Palermo, aimed to highlight those works of iron architecture made in Palermo at the turn of the century, with particular attention to the roofs which have suffered through the years the action of weather and, the consequences of neglect and superficiality regard these works and their role of historical, artistic and cultural evidence of the extraordinary Art Nouveau season in Sicily