Nrf2 Signaling: An Adaptive Response Pathway for Neurodegenerative Disorders

Oxidative damage contributes to pathogenesis in many neurodegenerative diseases. As the indicator and regulator of oxidative stress, the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway has been shown to have dynamic changes and examined for its neuroprotective role in many cases. Nrf2 is emerging as a regulatory protein in neuronal death, since it helps neuronal cells to meet with oxidative insults. In this chapter, we summarize the role of Nrf2 as a master regulator of oxidative stress. Furthermore, we treat some natural and chemical substances able to modulate the Nrf2 pathway and, therefore, their possible use in the neurodegenerative diseases therapeutic treatment

Energy refurbishment of historical buildings with public function: pilot case study

AbstractIn the last few decades, an increasing attention has been paid to the enhancement of energy performance and indoor comfort conditions of historical buildings, where the architectural heritage and artistic value do not allow typical retrofit intervention. The need to enhance the energy efficiency and environmental sustainability of historic buildings is addressed in this paper, through energy modeling and dynamic simulation of a real building with the integration of renewable energy plants for building heating and cooling. The pilot case study is "Palazzo Gallenga Stuart", a historical university building located in Perugia, Italy. The energy performance of the building has been evaluated in order to reduce the building energy demand through the implementation of high-efficiency technologies in historic buildings. The increase of the energy efficiency of the building has been pursued through the improvement of the actual energy plants' technology by introducing a more effective heat pump plant, in order to prevent the use of visually impacting external units on building historic façade

Lignin as co-product of second generation bioethanol production from ligno-cellulosic biomass

Abstract To improve the economic viability of the biofuel production from biomass, it is of increasing importance to add value to the lignin produced as a bio-residue. Moreover, to meet the goal to replace 30% of fossil fuel by biofuels by 2030, a huge amount of lignin will soon be produced. The first major step involved to add value to the unconverted lignin is its separation from other biomass constituents to give high purity lignin. In this current work, extraction of lignin from a bio-residue (containing ca. 40% lignin) from second generation bioethanol production is presented. The biomass chosen is Arundo donax L. (or giant reed), which is non-food plant, can tolerate a wide variety of ecological conditions with all types of soils, and has increasingly importance as raw material for industrial purposes as a source of fibers alternative to wood, which availability is decreasing. Slightly different extraction procedures are investigated. Methods used are simple, mild, safe, and avoid destruction of fiber content in the bio- residue, with the final aim to valorize all fractions of the bio-residue, which is an essential step to make biofuel production to be cost effective. Lignins extracted are characterized by morphological analysis, using Scanning Electron Microscopy, SEM, and in terms of thermal behavior -using thermo gravimetric analysis TGA- which is critical for determining suitability of the lignin for polymer composite preparation with improved thermomechanical performance. The method judged as the best of the three leads rapidly to extraction of lignin free from fibers and ash, with thermal behavior suitable for composite preparation

Gly482Ser PGC-1α gene polymorphism and exercise-related oxidative stress in amyotrophic lateral sclerosis patients

The role of exercise in Amyotrophic lateral sclerosis (ALS) pathogenesis is controversial and unclear. Exercise induces a pleiotropic adaptive response in skeletal muscle, largely through the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a transcriptional coactivator that regulates mitochondrial biogenesis and antioxidant defense mechanisms. It has been suggested that a Gly482Ser substitution in PGC-1α has functional relevance in human disorders and in athletic performance. To test this hypothesis, we examined the genotype distribution of PGC-1α Gly482Ser (1444 G > A) in ALS patients to evaluate whether or not the minor serine-encoding allele 482Ser is involved in oxidative stress responses during physical exercise. We genotyped 197 sporadic ALS patients and 197 healthy controls in order to detect differences in allelic frequencies and genotype distribution between the two groups. A total of 74 ALS patients and 65 controls were then comparatively assessed for plasmatic levels of the oxidative stress biomarkers, advanced oxidation protein products, ferric reducing ability and thiol groups. In addition a subgroup of 35 ALS patients were also assessed for total SOD and catalase plasmatic activity. Finally in 28 ALS patients we evaluated the plasmatic curve of the oxidative stress biomarkers and lactate during an incremental exercise test. No significant differences were observed in the genotype distribution and allelic frequency in ALS patients compared to the controls. We found significant increased advanced oxidation protein products (p A SNP, ALS patients with Gly482Ser allelic variant show increased exercise-related oxidative stress. This thus highlights the possible role of this antioxidant defense transcriptional coactivator in ALS

α-Synuclein Aggregates with β-Amyloid or Tau in Human Red Blood Cells: Correlation with Antioxidant Capability and Physical Exercise in Human Healthy Subjects

Neurodegenerative disorders (NDs) are characterized by abnormal accumulation/misfolding of specific proteins, primarily α-synuclein (α-syn), β-amyloid1–42 (Aβ), and tau, in both brain and peripheral tissue. In addition to homo-oligomers, the role of α-syn interactions with Aβ or tau has gradually emerged. The altered protein accumulation has been related to both oxidative stress and physical activity; nevertheless, no correlation among the presence of peripheral α-syn hetero-aggregates, antioxidant capacity, and physical exercise has been discovered as of yet. Herein, the content of α-syn, Aβ, tau, and of their heterocomplexes was determined in red blood cells (RBCs) of healthy subjects (sedentary and athletes). Such parameters were related to the extent of the antioxidant capability (AOC), a key marker of oxidative stress in aging-related pathologies, and to physical exercise, which is known to play an important preventive role in NDs and to modulate oxidative stress. Tau content and plasma AOC toward hydroxyl radicals were both reduced in older or sedentary subjects; in contrast, α-syn and Aβ accumulated in elderly subjects and showed an inverse correlation with both hydroxyl AOC and the level of physical activity. For the first time, α-syn heterocomplexes with Aβ or tau were quantified and demonstrated to be inversely related to hydroxyl AOC. Furthermore, α-syn/Aβ aggregates were significantly reduced in athletes and inversely correlated with physical activity level, independent of age. The positive correlation between antioxidant capability/physical activity and reduced protein accumulation was confirmed by these data and suggested that peripheral α-syn heterocomplexes may represent new indicators of ND-related protein misfolding

Lack of Association between Nuclear Factor ErythroidDerived 2-Like 2

Oxidative stress involvement has been strongly hypothesized among the possible pathogenic mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The intracellular redox balance is finely modulated by numerous complex mechanisms critical for cellular functions, among which the nuclear factor erythroid-derived 2-like 2 (NFE2L2/Nrf2) pathways. We genotyped, in a cohort of ALS patients ( = 145) and healthy controls ( = 168), three SNPs in Nrf2 gene promoter: −653 A/G, −651 G/A, and −617 C/A and evaluated, in a subset ( = 73) of patients, advanced oxidation protein products (AOPP), ironreducing ability of plasma (FRAP), and plasma thiols (-SH) as oxidative damage peripheral biomarkers. Nrf2 polymorphisms were not different among patients and controls. Increased levels of AOPP ( < 0.05) and decreased levels of FRAP ( < 0.001) have been observed in ALS patients compared with controls, but no difference in -SH values was found. Furthermore, no association was found between biochemical markers of redox balance and Nrf2 polymorphisms. These data confirm an altered redox balance in ALS and indicate that, while being abnormally modified compared to controls, the oxidative stress biomarkers assessed in this study are independent from the −65

α-Synuclein Heterocomplexes with β-Amyloid Are Increased in Red Blood Cells of Parkinson's Disease Patients and Correlate with Disease Severity

Neurodegenerative disorders (NDs) are characterized by abnormal accumulation/misfolding of specific proteins, primarily α-synuclein (α-syn), β-amyloid1-42(Aβ1-42) and tau, in both brain and peripheral tissues. In addition to oligomers, the role of the interactions of α-syn with Aβ or tau has gradually emerged. Nevertheless, despite intensive research, NDs have no accepted peripheral markers for biochemical diagnosis. In this respect, Red Blood Cells (RBCs) are emerging as a valid peripheral model for the study of aging-related pathologies. Herein, a small cohort (N= 28) of patients affected by Parkinson's disease (PD) and age-matched controls were enrolled to detect the content of α-syn (total and oligomeric), Aβ1-42and tau (total and phosphorylated) in RBCs. Moreover, the presence of α-syn association with tau and Aβ1-42was explored by co-immunoprecipitation/western blotting in the same cells, and quantitatively confirmed by immunoenzymatic assays. For the first time, PD patients were demonstrated to exhibit α-syn heterocomplexes with Aβ1-42and tau in peripheral tissues; interestingly, α-syn-Aβ1-42concentrations were increased in PD subjects with respect to healthy controls (HC), and directly correlated with disease severity and motor deficits. Moreover, total-α-syn levels were decreased in PD subjects and inversely related to their motor deficits. Finally, an increase of oligomeric-α-syn and phosphorylated-tau was observed in RBCs of the enrolled patients. The combination of three parameters (total-α-syn, phosphorylated-tau and α-syn-Aβ1-42concentrations) provided the best fitting predictive index for discriminating PD patients from controls. Nevertheless further investigations should be required, overall, these data suggest α-syn hetero-aggregates in RBCs as a putative tool for the diagnosis of PD

P2‐239: POTENTIAL DIAGNOSTIC VALUE OF RED BLOOD CELLS α‐SYNUCLEIN HETEROAGGREGATES IN ALZHEIMER'S DISEASE

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Evaluating the SERCA2 and VEGF mRNAs as Potential Molecular Biomarkers of the Onset and Progression in Huntington's Disease

Abnormalities of intracellular Ca2+ homeostasis and signalling as well as the down-regulation of neurotrophic factors in several areas of the central nervous system and in peripheral tissues are hallmarks of Huntington\u2019s disease (HD). As there is no therapy for this hereditary, neurodegenerative fatal disease, further effort should be made to slow the progression of neurodegeneration in patients through the definition of early therapeutic interventions. For this purpose, molecular biomarker(s) for monitoring disease onset and/or progression and response to treatment need to be identified. In the attempt to contribute to the research of peripheral candidate biomarkers in HD, we adopted a multiplex real-time PCR approach to analyse the mRNA level of targeted genes involved in the control of cellular calcium homeostasis and in neuroprotection. For this purpose we recruited a total of 110 subjects possessing the HD mutation at different clinical stages of the disease and 54 sex- and agematched controls. This study provides evidence of reduced transcript levels of sarco-endoplasmic reticulum-associated ATP2A2 calcium pump (SERCA2) and vascular endothelial growth factor (VEGF) in peripheral blood mononuclear cells (PBMCs) of manifest and premanifest HD subjects. Our results provide a potentially new candidate molecular biomarker for monitoring the progression of this disease and contribute to understanding some early events that might have a role in triggering cellular dysfunctions in HD

Spontaneous and induced aneuploidy in peripheral blood lymphocytes of patients with Alzheimer's disease.

Abstract This study was aimed at assessing whether peripheral blood lymphocytes of patients with Alzheimer’s disease (AD) show significant levels of aneuploidy and high percentages of cytogenetic events in vitro, indicating a predisposition to aneuploidy spontaneously, or after chemical treatment in vitro. A group of affected individuals and a group of unaffected, age-, sex- and smokinghabit- matched controls were identified. Lymphocytes were cultured for analysis of the following cytogenetic parameters: premature centromere division (PCD), satellite associations of acrocentric chromosomes (SA) and micronuclei (MN). In a subset of subjects, the fluorescence in situ hybridization (FISH) technique was combined with the MN assay, by means of a pancentromeric DNA probe for the detection of the presence of centric material. To evaluate the sensitivity to aneuploidogenic agents, in vitro treatment of lymphocytes of affected individuals was performed by adding griseofulvin, a chemical whose supposed target is microtubule-associated protein(s). Both the spontaneous frequency of MN and the frequency of PCD was significantly higher in patient cells than in controls. Furthermore, after application of the FISH technique, we found that the majority of MN were composed of whole chromosomes (because of the phenomenon of chromosome loss). Metaphase analysis for the detection of associative events between satellite regions of acrocentric chromosomes showed no differences between the two groups under study. Analysis of sensitivity to the aneuploidogen griseofulvin showed that the patient group was characterized by lower levels of MN induction compared with controls. Our data confirm that peripheral blood lymphocytes of AD patients are prone to undergo aneuploidy spontaneously in vitro and support the hypothesis that microtubule impairment might be associated with the disease