The predominant molecular symptom of aging is the accumulation of altered gene products. Moreover, several conditions including protein, lipid or glucose oxidation disrupt redox homeostasis and lead to accumulation of unfolded or misfolded proteins in the aging brain. Alzheimer's and Parkinson's diseases or Friedreich ataxia are neurological diseases sharing, as a common denominator, production of abnormal proteins, mitochondrial dysfunction and oxidative stress, which contribute to the pathogenesis of these so called "protein conformational diseases". The central nervous system has evolved the conserved mechanism of unfolded protein response to cope with the accumulation of misfolded proteins. As one of the main intracellular redox systems involved in neuroprotection, the vitagene system is emerging as a neurohormetic potential target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins (Hsp) Hsp70 and heme oxygenase-1, as well as thioredoxin reductase and sirtuins. Nutritional studies show that ageing in animals can be significantly influenced by dietary restriction. Thus, the impact of dietary factors on health and longevity is an increasingly appreciated area of research. Reducing energy intake by controlled caloric restriction or intermittent fasting increases lifespan and protects various tissues against disease. Genetics has revealed that ageing may be controlled by changes in intracellular NAD/NADH ratio regulating sirtuin, a group of proteins linked to aging, metabolism and stress tolerance in several organisms. Recent findings suggest that several phytochemicals exhibit biphasic dose responses on cells with low doses activating signaling pathways that result in increased expression of vitagenes encoding survival proteins, as in the case of the Keap1/Nrf2/ARE pathway activated by curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Consistently, the neuroprotective roles of dietary antioxidants including curcumin, acetyl-L-carnitine and carnosine have been demonstrated through the activation of these redox-sensitive intracellular pathways. Although the notion that stress proteins are neuroprotective is broadly accepted, still much work needs to be done in order to associate neuroprotection with specific pattern of stress responses. In this review the importance of vitagenes in the cellular stress response and the potential use of dietary antioxidants in the prevention and treatment of neurodegenerative disorders is discussed.

No abstract

This article discusses selected aspects of secondary brain injury after trauma and outlines key mechanisms associated with toxicity, oxidative stress, inflammation, and necrosis. Finally, this review discusses the role of different oxidants and presents potential clinically relevant molecular targets that could be harnessed to treat secondary injury associated with brain trauma.

Reduced expression and/or activity of antioxidant proteins lead to oxidative stress, accelerated aging and neurodegeneration. However, while excess reactive oxygen species (ROS) are toxic, regulated ROS play an important role in cell signaling. Perturbation of redox status, mutations favoring protein misfolding, altered glyc(osyl)ation, overloading of the product of polyunsaturated fatty acid peroxidation (hydroxynonenals, HNE) or cholesterol oxidation, can disrupt redox homeostasis. Collectively or individually these effects may impose stress and lead to accumulation of unfolded or misfolded proteins in brain cells. Alzheimer's (AD), Parkinson's and Huntington's disease, amyotrophic lateral sclerosis and Friedreich's ataxia are major neurological disorders associated with production of abnormally aggregated proteins and, as such, belong to the so-called "protein conformational diseases". The pathogenic aggregation of proteins in non-native conformation is generally associated with metabolic derangements and excessive production of ROS. The "unfolded protein response" has evolved to prevent accumulation of unfolded or misfolded proteins. Recent discoveries of the mechanisms of cellular stress signaling have led to new insights into the diverse processes that are regulated by cellular stress responses. The brain detects and overcomes oxidative stress by a complex network of "longevity assurance processes" integrated to the expression of genes termed vitagenes. Heat-shock proteins are highly conserved and facilitate correct protein folding. Heme oxygenase-1, an inducible and redox-regulated enzyme, has having an important role in cellular antioxidant defense. An emerging concept is neuroprotection afforded by heme oxygenase by its heme degrading activity and tissue-specific antioxidant effects, due to its products carbon monoxide and biliverdin, which is then reduced by biliverdin reductase in bilirubin. There is increasing interest in dietary compounds that can inhibit, retard or reverse the steps leading to neurodegeneration in AD. Specifically any dietary components that inhibit inappropriate inflammation, AbetaP oligomerization and consequent increased apoptosis are of particular interest, with respect to a chronic inflammatory response, brain injury and beta-amyloid associated pathology. Curcumin and ferulic acid, the first from the curry spice turmeric and the second a major constituent of fruit and vegetables, are candidates in this regard. Not only do these compounds serve as antioxidants but, in addition, they are strong inducers of the heat-shock response. Food supplementation with curcumin and ferulic acid are therefore being considered as a novel nutritional approach to reduce oxidative damage and amyloid pathology in AD. We review here some of the emerging concepts of pathways to neurodegeneration and how these may be overcome by a nutritional approach.

No abstract

Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive and memory decline, personality changes, and synapse loss. Increasing evidence indicates that factors such as oxidative and nitrosative stress, glutathione depletion, and impaired protein metabolism can interact in a vicious cycle, which is central to AD pathogenesis. In the present study, we demonstrate that brains of AD patients undergo oxidative changes classically associated with a strong induction of the so-called vitagenes, including the heat shock proteins (HSPs) heme oxygenase-1 (HO-1), HSP60, and HSP72, as well as thioredoxin reductase (TRXr). In inferior parietal brain of AD patients, a significant increase in the expression of HO-1 and TRXr was observed, whereas HO-2 expression was decreased, compared with controls. TRHr was not increased in AD cerebellum. Plasma GSH was decreased in AD patients, compared with the control group, and was associated with a significant increase in oxidative stress markers (i.e., GSSG, hydroxynonenal, protein carbonyl content, and nitrotyrosine). In AD lymphocytes, we observed an increased expression of inducible nitric oxide synthase, HO-1, Hsp72, HSP60, and TRXr. Our data support a role for nitrative stress in the pathogenesis of AD and indicate that the stress-responsive genes, such as HO-1 and TRXr, may represent important targets for novel cytoprotective strategies.

Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis that is associated with systemic in ammation. The aim of our study was to assess whether plasma markers of in ammation increased after exercise in patients with PAD. The study was conducted on two groups of 20 subjects each: one group (mean age 68.4 6 5.09 years) was affected by PAD with claudication, while the other group consisted of healthy controls (66.9 6 6.1 years). Concentrations of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFa) were determined in plasma, in supernatants and in cells stimulated with 1 mg lipopolysaccharide in all patients. E-selectin (ES), L-selectin (LS) and P-selectin (PS) concentrations and plasma concentrations of VCAM-1 and ICAM-I were also determined. All determinations were performed in patients at rest and after the treadmill exercise. Resting values of soluble mediators were greater in PAD patients than in controls. They increased in both groups after the treadmill test, even if posttreadmill concentrations were signi cantly higher in PAD patients (PAD p < 0.001 or 0.0001, controls p < 0.05 or 0.001).These results con rm that white blood cell activation is characteristic of systemic atherosclerosis and that these in ammation markers increase in conditions of hemodynamic stress.

In order to determine the mono- or oligosynaptic character of connections between pyramidal axons and individual spinal motor neurons, we constructed peri-stimulus time histograms (PSTHs) of the firing probability of voluntarily activated single motor units (SMUs) of various upper and lower limb muscles upon slightly suprathreshold transcranial anodal electrical stimulations of the motor cortex in normal subjects. Weak anodal cortical stimuli are known to activate preferentially fast-conducting pyramidal axons directly, bypassing cell bodies and cortical interneurons. A narrow bin width (0.1 ms) was chosen to measure precisely the duration of the PSTH excitatory peak, which corresponds to the rise time of the underlying compound excitatory post-synaptic potentials (EPSP). A short duration PSTH peak indicates sharp-rising EPSPs, most commonly encountered in the case of monosynaptic connections. In flexor carpi radialis and soleus SMUs, the PSTHs of built-in responses to anodal cortical stimuli were compared with those produced by 1A afferent stimulation able to elicit a Hoffmann reflex, which is known to be largely monosynaptic. In all upper and lower limb muscles, excitable SMUs responded to anodal cortical stimuli with a highly synchronized peak of increased firing probability. In flexor carpi radialis and soleus SMUs, the mean duration of this peak was significantly narrower than that evoked by 1A afferent stimulation, indicating that monosynaptic corticomotor neuronal transmission dominates low-threshold motor units, even in proximal arm and leg muscles. In the various muscles studied, and particularly in forearm SMUs, we did not observe broad PSTH peaks against the activation of non-monosynaptic corticomotor neuronal pathways, even with near-threshold stimuli. In some triceps and forearm flexor SMUs, subthreshold anodal pulses caused significant inhibition of their voluntary firing, with a latency consistent with activation of 1A inhibitory interneurons by the descending volleys. Measurements of the maximal number of counts in the excitatory PSTH peak upon anodal cortical stimuli provide comparisons of the strength of monosynaptic inputs to various muscles which seems to be maximal for hand and finger extensor muscles, and also for deltoid.