Redox modulation of cellular stress response and lipoxin A4 expression by Coriolus versicolor in rat brain: Relevance to Alzheimer's disease pathogenesis.

Increasing evidence supports the notion that oxidative stress-driven neuroinflammation is an early pathological feature in neurodegenerative diseases. As a prominent intracellular redox system involved in neuroprotection, the vitagene system is emerging as a potential neurohormetic target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins 70, heme oxygenase-1, thioredoxin and lipoxin A4. Emerging interest is now focusing on molecules capable of activating the vitagene system as novel therapeutic targets to minimize deleterious consequences associated with free radical-induced cell damage, such as in neurodegeneration. Mushroom-derived lipoxin A4 (LXA4) is an emerging endogenous eicosanoid able to promote resolution of inflammation, acting as an endogenous "braking signal" in the inflammatory process. Mushrooms have long been used in traditional medicine for thousands of years, being now increasingly recognized as rich source of polysaccharopeptides endowed with significant antitumor, antioxidant, antiviral, antibacterial and cytoprotective effects, thereby capable of stimulating host immune responses. Here we provide evidence of a neuroprotective action of the Coriolus mushroom when administered orally to rat. Expression of LXA4 was measured in different brain regions after oral administration of a Coriolus biomass preparation, given for 30 days. LXA4 up-regulation was associated with an increased content of redox sensitive proteins involved in cellular stress response, such as Hsp72, heme oxygenase-1 and thioredoxin. In the brain of rats receiving Coriolus, maximum induction of LXA4 was observed in cortex and hippocampus. Hsps induction was associated with no significant changes in IkBα, NFkB and COX-2 brain levels. Conceivably, activation of LXA4 signaling and modulation of stress-responsive vitagene proteins could serve as a potential therapeutic target for AD-related inflammation and neurodegenerative damage.

Analytical approaches to the diagnosis and treatment of aging and aging-related disease: redox status and proteomics.

Basal levels of oxidants are indispensible for redox signaling to produce adaptive cellular responses such as vitagenes linked to cell survival; however, at higher levels, they are detrimental to cells, contributing to aging and to the pathogenesis of numerous age-related diseases. Aging is a complex systemic process and the major gap in aging research reminds the insufficient knowledge about pathways shifting from normal "healthy" aging to disease-associated pathological aging. The major complication of normal "healthy" aging is in fact the increasing risk of age-related diseases such as cardiovascular diseases, diabetes mellitus, and neurodegenerative pathologies that can adversely affect the quality of life in general, with enhanced incidences of comorbidities and mortality. In this context, global "omics" approaches may help to dissect and fully study the cellular and molecular mechanisms of aging and age-associated processes. The proteome, being more close to the phenotype than the transcriptome and more stable than the metabolome, represents the most promising "omics" field in aging research. In the present study, we exploit recent advances in the redox biology of aging and discuss the potential of proteomics approaches as innovative tools for monitoring at the proteome level the extent of protein oxidative insult and related modifications with the identification of targeted proteins.

Sex hormonal regulation and hormesis in aging and longevity: role of vitagenes.

Aging process is accompanied by hormonal changes characterized by an imbalance between catabolic hormones, such as cortisol and thyroid hormones which remain stable and hormones with anabolic effects (testosterone, insulin like growth factor-1 (IGF-1) and dehydroepiandrosterone sulphate (DHEAS), that decrease with age. Deficiencies in multiple anabolic hormones have been shown to predict health status and longevity in older persons.Unlike female menopause, which is accompanied by an abrupt and permanent cessation of ovarian function (both folliculogenesis and estradiol production), male aging does not result in either cessation of testosterone production nor infertility. Although the circulating serum testosterone concentration does decline with aging, in most men this decrease is small, resulting in levels that are generally within the normal range. Hormone therapy (HT) trials have caused both apprehension and confusion about the overall risks and benefits associated with HT treatment. Stress-response hormesis from a molecular genetic perspective corresponds to the induction by stressors of an adaptive, defensive response, particularly through alteration of gene expression. Increased longevity can be associated with greater resistance to a range of stressors. During aging, a gradual decline in potency of the heat shock response occur and this may prevent repair of protein damage. Conversely, thermal stress or pharmacological agents capable of inducing stress responses, by promoting increased expression of heat-shock proteins, confer protection against denaturation of proteins and restoration of proteome function. If induction of stress resistance increases life span and hormesis induces stress resistance, hormesis most likely result in increased life span. Hormesis describes an adaptive response to continuous cellular stresses, representing a phenomenon where exposure to a mild stressor confers resistance to subsequent, otherwise harmful, conditions of increased stress. This biphasic dose-response relationship, displaying low-dose stimulation and a high-dose inhibition, as adaptive response to detrimental lifestyle factors determines the extent of protection from progression to metabolic diseases such as diabetes and more in general to hormonal dysregulation and age-related pathologies. Integrated responses exist to detect and control diverse forms of stress. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed vitagenes. Vitagenes encode for heat shock proteins (Hsps), thioredoxin and sirtuin protein systems. Nutritional antioxidants, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways under control of Vitagene protein network. Here we focus on possible signaling mechanisms involved in the activation of vitagenes resulting in enhanced defense against functional defects leading to degeneration and cell death with consequent impact on longevity processes.