BBA - Molecular Basis of Disease (v.1822, #5)

Antioxidants and antioxidant treatment in disease by D. Allan Butterfield; Jeffrey N. Keller (615).

Natural substances and Alzheimer's disease: From preclinical studies to evidence based medicine by Cesare Mancuso; Raffaella Siciliano; Eugenio Barone; Paolo Preziosi (616-624).
Over the last 10 years, the potential therapeutic effects of nutraceuticals to prevent or delay Alzheimer's disease were proposed. Among dietary antioxidants curcumin, Ginkgo biloba and carnitines were extensively studied for their neuroprotective effects. The rationale for this alternative therapeutic approach was based on several preclinical studies which suggested the neuroprotective effects for curcumin, Ginkgo biloba and acetyl-l-carnitine due to either a free radical scavenging activity or the inhibition of pro-inflammatory pathways or the potentiation of the cell stress response. However, although these are interesting premises, clinical studies were not able to demonstrate significant beneficial effects of curcumin, Ginkgo biloba and acetyl-l-carnitine in improving cognitive functions in Alzheimer's disease patients. The aim of this review is to summarize the main pharmacologic features of curcumin, Ginkgo biloba and carnitines as well as to underlie the main outcomes reached by clinical studies designed to demonstrate the efficacy of these natural substances in Alzheimer's disease patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.► Alzheimer's disease may benefit of antioxidant treatment. ► Curcumin, Ginkgo biloba and carnitines were neuroprotective in preclinical studies. ► Clinical evidence only partially confirmed preclinical studies.
Keywords: Acetyl-l-carnitine; Alzheimer's disease; Curcumin; Ginkgo biloba; Pharmacodynamics; Pharmacokinetics;

Elevation of glutathione as a therapeutic strategy in Alzheimer disease by Chava B. Pocernich; D. Allan Butterfield (625-630).
Oxidative stress has been associated with the onset and progression of mild cognitive impairment (MCI) and Alzheimer disease (AD). AD and MCI brain and plasma display extensive oxidative stress as indexed by protein oxidation, lipid peroxidation, free radical formation, DNA oxidation, and decreased antioxidants. The most abundant endogenous antioxidant, glutathione, plays a significant role in combating oxidative stress. The ratio of oxidized to reduced glutathione is utilized as a measure of intensity of oxidative stress. Antioxidants have long been considered as an approach to slow down AD progression. In this review, we focus on the elevation on glutathione through N-acetyl-cysteine (NAC) and γ-glutamylcysteine ethyl ester (GCEE) as a potential therapeutic approach for Alzheimer disease. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.►Glutathione (GSH) is the most abundant endogenous antioxidant in brain. ►Oxidative stress is a prominent feature of Alzheimer disease and MCI brain. ►Elevation of GSH in vivo protects brain against AD-relevant A beta(1–42). ►Elevation of GSH in brain induces several protective pathways.
Keywords: Alzheimer disease (AD); Mild cognitive impairment (MCI); Amyloid β-peptide; Glutathione (GSH); N-acetylcysteine (NAC); γ-Glutamylcysteine ethyl ester;

Antioxidant clinical trials in mild cognitive impairment and Alzheimer's disease by Patrizia Mecocci; Maria Cristina Polidori (631-638).
Alzheimer's disease (AD) is a highly disabling progressive neurodegenerative disorder characterized by a steadily growing number of patients, by the absence of a cure for the disease and by great difficulties in diagnosing in the preclinical phase. Progresses in defining the complex etiopathogenesis of AD consider oxidative stress a core aspect as far as both AD onset and progression are concerned. However, clinical trials of antioxidants in AD have brought conflicting conclusions. In this review, we report the main results of clinical trials with antioxidants in mild cognitive impairment (MCI) and AD. Although available data do not warrant the doubtless use of antioxidants in AD, they are characterized by extremely poor comparability and the absence of a substantial clinical benefit of antioxidants in AD is not disproved to date. Furthermore, the role of vascular damage that contributes to oxidative stress in AD should be addressed in testing antioxidant treatments. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.► Oxidative damage is one of the main etiopathogenetic factors of Alzheimer's disease. ► Antioxidants have been proposed for AD prevention and therapy. ► Observational studies with dietary or supplemented antioxidants showed benefits. ► Clinical trials with antioxidants have led to conflicting results. ► New compounds alone or in association are under study in ongoing trials.
Keywords: Clinical trial; Antioxidant; Oxidative stress; Free radical; Alzheimer's disease; Mild cognitive impairment;

Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer's disease: Implications to mitochondria-targeted antioxidant therapeutics by P. Hemachandra Reddy; Raghav Tripathi; Quang Troung; Karuna Tirumala; Tejaswini P. Reddy; Vishwanath Anekonda; Ulziibat P. Shirendeb; Marcus J. Calkins; Arubala P. Reddy; Peizhong Mao; Maria Manczak (639-649).
Synaptic pathology and mitochondrial oxidative damage are early events in Alzheimer's disease (AD) progression. Loss of synapses and synaptic damage are the best correlates of cognitive deficits found in AD patients. Recent research on amyloid beta (Aβ) and mitochondria in AD revealed that Aβ accumulates in synapses and synaptic mitochondria, leading to abnormal mitochondrial dynamics and synaptic degeneration in AD neurons. Further, recent studies using live-cell imaging and primary neurons from amyloid beta precursor protein (AβPP) transgenic mice revealed reduced mitochondrial mass, defective axonal transport of mitochondria and synaptic degeneration, indicating that Aβ is responsible for mitochondrial and synaptic deficiencies. Tremendous progress has been made in studying antioxidant approaches in mouse models of AD and clinical trials of AD patients. This article highlights the recent developments made in Aβ-induced abnormal mitochondrial dynamics, defective mitochondrial biogenesis, impaired axonal transport and synaptic deficiencies in AD. This article also focuses on mitochondrial approaches in treating AD, and also discusses latest research on mitochondria-targeted antioxidants in AD. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.► Summarizes recent developments of Abeta-induced abnormal mitochondrial dynamics and synaptic degeneration in AD. ► Discussed the factors that cause mitochondrial dysfunction in AD. ► Highlighted the antioxidant approaches in AD. ► Discussed the mitochondria-targeted antioxidant therapeutics in AD.
Keywords: Alzheimer's disease; Antioxidant; Primary neuron; Reactive oxygen species; Amyloid beta; Amyloid precursor protein;

The senescence accelerated mouse (SAMP8) as a model for oxidative stress and Alzheimer's disease by John E. Morley; Harvey James Armbrecht; Susan A. Farr; Vijaya B. Kumar (650-656).
The senescence accelerated mouse (SAMP8) is a spontaneous animal model of overproduction of amyloid precursor protein (APP) and oxidative damage. It develops early memory disturbances and changes in the blood–brain barrier resulting in decreased efflux of amyloid-β protein from the brain. It has a marked increase in oxidative stress in the brain. Pharmacological treatments that reduce oxidative stress improve memory. Treatments that reduce amyloid-β (antisense to APP and antibodies to amyloid-β) not only improve memory but reduce oxidative stress. Early changes in lipid peroxidative damage favor mitochondrial dysfunction as being a trigger for amyloid-β overproduction in this genetically susceptible mouse strain. This sets in motion a cycle where the increased amyloid-beta further damages mitochondria. We suggest that this should be termed the Inflammatory-Amyloid Cycle and may well be similar to the mechanisms responsible for the pathophysiology of Alzheimer's disease. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.► Oxidative damage to neuronal cells may influence the pathogenesis of Alzheimer's disease. ► SAMP8 mouse—an excellent model to study Aβ overproduction/oxidative damage to brain tissue. ► Aβ overproduction can trigger what becomes a vicious cycle. ► Mitochondrial dysfunction resulting in inflammation can result in a vicious cycle. ► Low dose Aβ—physiologically important to memory and protects neurons from oxidative damage.
Keywords: Senescence accelerated mouse (SAMP8); Oxidative damage; Alzheimer's disease; Blood–brain barrier; Amyloid-beta;

Antioxidants in Down syndrome by Ira T. Lott (657-663).
Individuals with Down syndrome (DS) have high levels of oxidative stress throughout the lifespan. Mouse models of DS share some structural and functional abnormalities that parallel findings seen in the human phenotype. Several of the mouse models show evidence of cellular oxidative stress and have provided a platform for antioxidant intervention. Genes that are overexpressed on chromosome 21 are associated with oxidative stress and neuronal apoptosis. The lack of balance in the metabolism of free radicals generated during processes related to oxidative stress may have a direct role in producing the neuropathology of DS including the tendency to Alzheimer disease (AD). Mitochondria are often a target for oxidative stress and are considered to be a trigger for the onset of the AD process in DS. Biomarkers for oxidative stress have been described in DS and in AD in the general population. However, intervention trials using standard antioxidant supplements or diets have failed to produce uniform therapeutic effect. This chapter will examine the biological role of oxidative stress in DS and its relationship to abnormalities in both development and aging within the disorder. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.► Individuals with Down syndrome have high levels of oxidative stress throughout life. ► Oxidative stress may play role in pathogenesis of Alzheimer disease in Down syndrome. ► Mitochondrial dysfunction occurs at early age in Down syndrome. ► Mitochondrial dysfunction is impacted by and creates oxidative stress. ► Prophylactic interventions with antioxidant supplements might be beneficial.
Keywords: Antioxidant; Oxidative stress; Down syndrome; Alzheimer disease; Antioxidant clinical trial; Mitochondrial disorder;

Antioxidants in Huntington's disease by Ashu Johri; M. Flint Beal (664-674).
Huntington's disease (HD) is a prototypical neurodegenerative disease in which there is selective neuronal degeneration, which leads to progressive disability, manifesting itself as a movement disorder, with both psychiatric and cognitive impairment. The disease is caused by a cytosine–adenine–guanine (CAG) repeat expansion in the huntingtin gene, which causes an expanded polyglutamine repeat in the huntingtin protein, resulting in a protein with a novel gain of function. The mutant huntingtin protein causes neuronal dysfunction and eventual cell death in which transcriptional impairment, excitotoxicity, oxidative damage, inflammation, apoptosis and mitochondrial dysfunction are all implicated. A critical transcriptional impairment may be impaired expression and function of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), a master co-regulator of mitochondrial biogenesis and expression of antioxidant enzymes. A deficiency of PGC-1α leads to increased vulnerability to oxidative stress and to striatal degeneration. The extent and severity of the oxidative damage in HD are features well recognized but perhaps underappreciated. Oxidative damage occurs to lipids, proteins and deoxyribonucleic acid (DNA), and it has been suggested that the latter may contribute to CAG repeat expansion during DNA repair . A marked elevation of oxidized DNA bases occurs in patients' plasma, which may provide a biomarker of disease progression. Antioxidants are effective in slowing disease progression in transgenic mouse models of HD, and show promise in human clinical trials. Strategies to transcriptionally increase expression of antioxidant enzymes by modulating the Nrf-2/ARE pathway, or by increasing expression of PGC-1α hold great promise for developing new treatments to slow or halt the progression of HD. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.► Huntington's disease (HD) is a progressively debilitating neurodegenerative disease. ► Mitochondrial biogenesis, PGC-1α expression and antioxidant system are impaired in HD. ► The extent and severity of the oxidative damage in HD are well recognized. ► Modulating PGC-1α is beneficial in boosting mitochondrial and antioxidant functions. ► Mitochondria targeted antioxidant therapies hold great promise for treatment of HD.
Keywords: Huntington's disease; Antioxidant; PGC-1alpha;

Antioxidant therapies in traumatic brain and spinal cord injury by Mona Bains; Edward D. Hall (675-684).
Free radical formation and oxidative damage have been extensively investigated and validated as important contributors to the pathophysiology of acute central nervous system injury. The generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is an early event following injury occurring within minutes of mechanical impact. A key component in this event is peroxynitrite-induced lipid peroxidation. As discussed in this review, peroxynitrite formation and lipid peroxidation irreversibly damages neuronal membrane lipids and protein function, which results in subsequent disruptions in ion homeostasis, glutamate-mediated excitotoxicity, mitochondrial respiratory failure and microvascular damage. Antioxidant approaches include the inhibition and/or scavenging of superoxide, peroxynitrite, or carbonyl compounds, the inhibition of lipid peroxidation and the targeting of the endogenous antioxidant defense system. This review covers the preclinical and clinical literature supporting the role of ROS and RNS and their derived oxygen free radicals in the secondary injury response following acute traumatic brain injury (TBI) and spinal cord injury (SCI) and reviews the past and current trends in the development of antioxidant therapeutic strategies. Combinatorial treatment with the suggested mechanistically complementary antioxidants will also be discussed as a promising neuroprotective approach in TBI and SCI therapeutic research. This article is part of a Special Issue entitled: Antioxidants and antioxidant treatment in disease.► Free radical-induced oxidative damage is a well-established hallmark of central nervous system injury. ► Peroxynitrite formation and lipid peroxidation are two key biochemical events of radical-induced secondary injury. ► Current therapies for traumatic brain and spinal cord injury are limited despite advances in preclinical research. ► Improved antioxidant approaches are necessary for the success of future clinical trials.
Keywords: Antioxidant; Reactive oxygen species; Oxidative damage; Traumatic brain injury; Spinal cord injury; Lipid peroxidation;

Antioxidants in the canine model of human aging by Amy L.S. Dowling; Elizabeth Head (685-689).
Oxidative damage can lead to neuronal dysfunction in the brain due to modifications to proteins, lipids and DNA/RNA. In both human and canine brain, oxidative damage progressively increases with age. In the Alzheimer's disease (AD) brain, oxidative damage is further exacerbated, possibly due to increased deposition of beta-amyloid (Aβ) peptide in senile plaques. These observations have led to the hypothesis that antioxidants may be beneficial for brain aging and AD. Aged dogs naturally develop AD-like neuropathology (Aβ) and cognitive dysfunction and are a useful animal model in which to test antioxidants. In a longitudinal study of aging beagles, a diet rich in antioxidants improved cognition, maintained cognition and reduced oxidative damage and Aβ pathology in treated animals. These data suggest that antioxidants may be beneficial for human brain aging and for AD, particularly as a preventative intervention. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.► Oxidative damage increases with brain aging. ► Aged dogs naturally develop cognitive decline and brain pathology. ► Antioxidants improve cognition and reduce neuropathology in aging dogs. ► Antioxidants may be beneficial for human brain aging and Alzheimer's disease.
Keywords: Alzheimer's disease; Beta-amyloid; Cognition; Dog; Lipoic acid; Vitamins;

Oxidative stress and antioxidant therapy in cystic fibrosis by Francesco Galli; Andrea Battistoni; Roberto Gambari; Alfonso Pompella; Alessandra Bragonzi; Francesca Pilolli; Luigi Iuliano; Marta Piroddi; Maria Cristina Dechecchi; Giulio Cabrini (690-713).
Cystic fibrosis is a lethal autosomal recessive condition caused by a defect of the transmembrane conductance regulator gene that has a key role in cell homeostasis. A dysfunctional cystic fibrosis transmembrane conductance regulator impairs the efflux of cell anions such as chloride and bicarbonate, and also that of other solutes such as reduced glutathione. This defect produces an increased viscosity of secretions together with other metabolic defects of epithelia that ultimately promote the obstruction and fibrosis of organs. Recurrent pulmonary infections and respiratory dysfunction are main clinical consequences of these pathogenetic events, followed by pancreatic and liver insufficiency, diabetes, protein-energy malnutrition, etc. This complex comorbidity is associated with the extensive injury of different biomolecular targets by reactive oxygen species, which is the biochemical hallmark of oxidative stress. These biological lesions are particularly pronounced in the lung, in which the extent of oxidative markers parallels that of inflammatory markers between chronic events and acute exacerbations along the progression of the disease. Herein, an abnormal flux of reactive oxygen species is present by the sustained activation of neutrophils and other cystic fibrosis-derived defects in the homeostatic processes of pulmonary epithelia and lining fluids. A sub-optimal antioxidant protection is believed to represent a main contributor to oxidative stress and to the poor control of immuno-inflammatory pathways in these patients. Observed defects include an impaired reduced glutathione metabolism and lowered intake and absorption of fat-soluble antioxidants (vitamin E, carotenoids, coenzyme Q-10, some polyunsaturated fatty acids, etc.) and oligoelements (such as Se, Cu and Zn) that are involved in reactive oxygen species detoxification by means of enzymatic defenses. Oral supplements and aerosolized formulations of thiols have been used in the antioxidant therapy of this inherited disease with the main aim of reducing the extent of oxidative lesions and the rate of lung deterioration. Despite positive effects on laboratory end points, poor evidence was obtained on the side of clinical outcome so far. These aspects examined in this critical review of the literature clearly suggest that further and more rigorous trials are needed together with new generations of pharmacological tools to a more effective antioxidant and anti-inflammatory therapy of cystic fibrosis patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.► Cystic fibrosis is a genetic disorder associated with inflammation and its accompanying oxidative stress. ► A sub-optimal antioxidant protection is observed as a cause of oxidative stress in CF. ► Novel antioxidant strategies are expected to affect the clinical outcome in CF. ► Randomized controlled trials are needed to further explore antioxidant therapy in CF.
Keywords: Cystic fibrosis; Antioxidant; Oxidative stress; Reactive oxygen species; Inflammation; Glutathione;

Cigarette/tobacco smoke/biomass fuel-induced oxidative and aldehyde/carbonyl stress are intimately associated with the progression and exacerbation of chronic obstructive pulmonary disease (COPD). Therefore, targeting systemic and local oxidative stress with antioxidants/redox modulating agents, or boosting the endogenous levels of antioxidants are likely to have beneficial effects in the treatment/management of COPD. Various antioxidant agents, such as thiol molecules (glutathione and mucolytic drugs, such as N-acetyl-L-cysteine and N-acystelyn, erdosteine, fudosteine, ergothioneine, and carbocysteine), have been reported to modulate various cellular and biochemical aspects of COPD. These antioxidants have been found to scavenge and detoxify free radicals and oxidants, regulate of glutathione biosynthesis, control nuclear factor-kappaB (NF-kappaB) activation, and hence inhibiting inflammatory gene expression. Synthetic molecules, such as specific spin traps like α-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (ECSOD mimetic), porphyrins (AEOL 10150 and AEOL 10113), and a superoxide dismutase mimetic M40419, iNOS and myeloperoxidase inhibitors, lipid peroxidation inhibitors/blockers edaravone, and lazaroids/tirilazad have also been shown to have beneficial effects by inhibiting cigarette smoke-induced inflammatory responses and other carbonyl/oxidative stress-induced cellular alterations. A variety of oxidants, free radicals, and carbonyls/aldehydes are implicated in the pathogenesis of COPD, it is therefore, possible that therapeutic administration or supplementation of multiple antioxidants and/or boosting the endogenous levels of antioxidants will be beneficial in the treatment of COPD. This review discusses various novel pharmacological approaches adopted to enhance lung antioxidant levels, and various emerging beneficial and/or prophylactic effects of antioxidant therapeutics in halting or intervening the progression of COPD. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.► Cigarette smoke causes oxidative stress in COPD. ► Antioxidants are likely to have beneficial effects in management of COPD. ► Thiols, enzyme mimetics, spin traps, and porphyrins are therapeutic agents. ► Antioxidants have pharmacological effects in inhibiting cellular processes in COPD.
Keywords: Tobacco smoke; Antioxidants; Oxidants; Glutathione; Nrf2; Chronic Obstructive Pulmonary Disease;

Oxidative stress, glutathione status, sirtuin and cellular stress response in type 2 diabetes by V. Calabrese; C. Cornelius; V. Leso; A. Trovato-Salinaro; B. Ventimiglia; M. Cavallaro; M. Scuto; S. Rizza; L. Zanoli; S. Neri; P. Castellino (729-736).
Oxidative stress has been suggested to play a main role in the pathogenesis of type 2 diabetes mellitus and its complications. As a consequence of this increased oxidative status a cellular adaptive response occurs requiring functional chaperones, antioxidant production and protein degradation. This study was designed to evaluate systemic oxidative stress and cellular stress response in patients suffering from type 2 diabetes and in age-matched healthy subjects. Systemic oxidative stress has been evaluated by measuring plasma reduced and oxidized glutathione, as well as pentosidine, protein carbonyls lipid oxidation products 4-hydroxy-2-nonenal and F2-isoprostanes in plasma, and lymphocytes, whereas the lymphocyte levels of the heat shock proteins (HSP) HO-1, Hsp72, Sirtuin-1, Sirtuin-2 and thioredoxin reductase-1 (TrxR-1) have been measured to evaluate the systemic cellular stress response. Plasma GSH/GSSG showed a significant decrease in type 2 diabetes as compared to control group, associated with increased pentosidine, F2-isoprostanes, carbonyls and HNE levels. In addition, lymphocyte levels of HO-1, Hsp70, Trx and TrxR-1 (P < 0.05 and P < 0.01) in diabetic patients were higher than in normal subjects, while sirtuin-1 and sirtuin-2 protein was significantly decreased (p < 0.05). In conclusion, patients affected by type 2 diabetes are under condition of systemic oxidative stress and, although the relevance of downregulation in sirtuin signal has to be fully understood, however induction of HSPs and thioredoxin protein system represent a maintained response in counteracting systemic pro-oxidant status. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.Display Omitted► Oxidative stress plays a key role in diabetes mellitus and its complications. ► This study evaluates oxidative stress and stress response in diabetic patients. ► Sirtuin and Hsp signals counteract systemic oxidant status.
Keywords: Type 2 diabetes; Redox signaling; Cellular stress response; Glutathione status; Sirtuins; Vitagenes;

Antioxidants in cervical cancer: Chemopreventive and chemotherapeutic effects of polyphenols by F. Di Domenico; C. Foppoli; R. Coccia; M. Perluigi (737-747).
Cervical cancer lesions are a major threat to the health of women, representing the second most common cancer worldwide. The unanimously recognized etiological factor in the causation of cervical cancer is the infection with human papilloma virus (HPV). HPV infection, although necessary, is not per se sufficient to induce cancer. Other factors have to be involved in the progression of infected cells to the full neoplastic phenotype. Oxidative stress represents an interesting and under-explored candidate as a promoting factor in HPV-initiated carcinogenesis. Oxidative stress is known to perturb the cellular redox status thus leading to alteration of gene expression responses through the activation of several redox-sensitive transcription factors. This signaling cascade affects both cell growth and cell death. The ability of naturally occurring antioxidants to modulate cellular signal transduction pathways, through the activation/repression of multiple redox-sensitive transcription factors, has been claimed for their potential therapeutic use as chemopreventive agents. Among these compounds, polyphenols have been found to be promising agents toward cervical cancer. In addition to acting as antioxidants, polyphenols display a wide variety of biological function including induction of apoptosis, growth arrest, inhibition of DNA synthesis and modulation of signal transduction pathways. They can interfere with each stage of carcinogenesis initiation, promotion and progression to prevent cancer development. The present review discusses current knowledge of the major molecular pathways, which are involved in HPV-driven cancerogenesis, and the ability of polyphenols to modulate these pathways. By acting at specific steps of viral transformation cascade, polyphenols have been demonstrated to selectively inhibit tumor cell growth and may be a promising therapeutic tool for treatment of cervical cancer. In addition, recent results obtained in clinical trials using polyphenols are also discussed. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.► Cervical cancer is the second most common cancer among women worldwide and represents a major concern for public health. ► Oxidative stress is a candidate factor involved in the pathogenesis and progression of cervical cancer. ► Polyphenols have been found to be promising agents toward cervical cancer. ► In addition to act as antioxidants, polyphenols display a wide variety of biological functions. ► Polyphenols were demonstrated to inhibit the proliferation of HPV-positive cancer cells.
Keywords: Cervical cancer; HPV; Polyphenol; Apoptosis; Oxidative stress;

Oxidative stress is involved in the onset, progression and pathogenesis of a number of diseases including neurodegenerative diseases. It is critical to develop a pharmacological approach to combat oxidative stress which may reduce the risk of diseases and help in promoting healthy life. In an attempt to reduce the side effects associated with allopathic medicines a number of studies are now focusing on developing treatment regimens from naturally occurring plant products. In this review, the protective role of ferulic acid (4-hydroxy-3-methoxycinnamic acid) (FA), a naturally occurring antioxidant compound found in fruit, some vegetables, and grains, and its ethyl ester derivative are discussed with respect to neurodegeneration. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.► Oxidative stress is involved in neurodegenerative diseases. ► Natural antioxidants may protect against oxidative stress related neurodegenerative diseases. ► Ferulic acid (FA) is a naturally occurring antioxidant. ► Use of FA and ferulic acid ethyl ester might limit the side effects associated with drugs.
Keywords: Oxidative stress; Neurodegenerative disease; Nutraceutical; Free radical; Ferulic acid; Ferulic acid ethyl ester;

Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity by Vittorio Calabrese; Carolin Cornelius; Albena T. Dinkova-Kostova; Ivo Iavicoli; Rosanna Di Paola; Aleardo Koverech; Salvatore Cuzzocrea; Enrico Rizzarelli; Edward J. Calabrese (753-783).
Modulation of endogenous cellular defense mechanisms represents an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as in neurodegeneration. This paper introduces the emerging role of exogenous molecules in hormetic-based neuroprotection and the mitochondrial redox signaling concept of hormesis and its applications to the field of neuroprotection and longevity. Maintenance of optimal long-term health conditions is accomplished by a complex network of longevity assurance processes that are controlled by vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. Dietary antioxidants, such as polyphenols and L-carnitine/acetyl-L-carnitine, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. Hormesis provides the central underpinning of neuroprotective responses, providing a framework for explaining the common quantitative features of their dose response relationships, their mechanistic foundations, their relationship to the concept of biological plasticity as well as providing a key insight for improving the accuracy of the therapeutic dose of pharmaceutical agents within the highly heterogeneous human population. This paper describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways including sirtuin, Nrfs and related pathways that integrate adaptive stress responses in the prevention of neurodegenerative diseases. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.Display Omitted► Modulation of endogenous cellular defense mechanisms in neurodegenerative diseases. ► Network of longevity assurance processes that are controlled by vitagenes. ► Nrf2 pathway integrates stress responses in the prevention of neurodegeneration.
Keywords: Hormesis; Antioxidant; Redox signaling; Cellular stress response; Mitochondria; Vitagene;

Since its discovery, the unique properties of the naturally occurring amino acid, L-ergothioneine (EGT; 2-mercaptohistidine trimethylbetaine), have intrigued researchers for more than a century. This widely distributed thione is only known to be synthesized by non-yeast fungi, mycobacteria and cyanobacteria but accumulates in higher organisms at up to millimolar levels via an organic cation transporter (OCTN1). The physiological role of EGT has yet to be established. Numerous in vitro assays have demonstrated the antioxidant and cytoprotective capabilities of EGT against a wide range of cellular stressors, but an antioxidant role has yet to be fully verified in vivo. Nevertheless the accumulation, tissue distribution and scavenging properties, all highlight the potential for EGT to function as a physiological antioxidant. This article reviews our current state of knowledge. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.►This review summarizes our current state of knowledge on ergothioneine. ►Ergothioneine has demonstrated antioxidant and cytoprotective capacities in vitro. ►These functions may highlight therapeutic benefits against numerous conditions in humans. ►The true function of ergothioneine in vivo has not yet been identified. ►Numerous hypotheses are examined.
Keywords: Ergothioneine; Antioxidant; Organic cation transporter; Thiol; Oxidative stress;

Manganese superoxide dismutase, MnSOD and its mimics by Sumitra Miriyala; Ivan Spasojevic; Artak Tovmasyan; Daniela Salvemini; Zeljko Vujaskovic; Daret St. Clair; Ines Batinic-Haberle (794-814).
Increased understanding of the role of mitochondria under physiological and pathological conditions parallels increased exploration of synthetic and natural compounds able to mimic MnSOD — endogenous mitochondrial antioxidant defense essential for the existence of virtually all aerobic organisms from bacteria to humans. This review describes most successful mitochondrially-targeted redox-active compounds, Mn porphyrins and MitoQ10 in detail, and briefly addresses several other compounds that are either catalysts of O2 dismutation, or its non-catalytic scavengers, and that reportedly attenuate mitochondrial dysfunction. While not a true catalyst (SOD mimic) of O2 dismutation, MitoQ10 oxidizes O2 to O2 with a high rate constant. In vivo it is readily reduced to quinol, MitoQH2, which in turn reduces ONOO to NO2, producing semiquinone radical that subsequently dismutes to MitoQ10 and MitoQH2, completing the “catalytic” cycle. In MitoQ10, the redox-active unit was coupled via 10-carbon atom alkyl chain to monocationic triphenylphosphonium ion in order to reach the mitochondria. Mn porphyrin-based SOD mimics, however, were designed so that their multiple cationic charge and alkyl chains determine both their remarkable SOD potency and carry them into the mitochondria. Several animal efficacy studies such as skin carcinogenesis and UVB-mediated mtDNA damage, and subcellular distribution studies of Saccharomyces cerevisiae and mouse heart provided unambiguous evidence that Mn porphyrins mimic the site and action of MnSOD, which in turn contributes to their efficacy in numerous in vitro and in vivo models of oxidative stress. Within a class of Mn porphyrins, lipophilic analogs are particularly effective for treating central nervous system injuries where mitochondria play key role. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.► MnSOD action was briefly summarized and compared to the action of its mimics. ► Mn porphyrins and MitoQ were described in details. ► Cationic Mn(III) N-alkylpyridylporphyrins mimic both the catalytic action and location of MnSOD. ► MitoQ accumulates in mitochondria and scavenges superoxide stoichiometrically.
Keywords: MnSOD mimics; MnSOD; MitoQ; Mn porphyrins; MnTE-2-PyP; MnTnHex-2-PyP;

Anti-superoxide and anti-peroxynitrite strategies in pain suppression by Kali Janes; William L. Neumann; Daniela Salvemini (815-821).
Superoxide (SO, O2·) and its reaction product peroxynitrite (PN, ONOO) have been shown to be important in the development of pain of several etiologies. While significant progress has been made in teasing out the relative contribution of SO and PN peripherally, spinally, and supraspinally during the development and maintenance of central sensitization and pain, there is still a considerable void in our understanding. Further research is required in order to develop improved therapeutic strategies for selectively eliminating SO and/or PN. Furthermore, it may be that PN is a more attractive target, in that unlike SO it has no currently known beneficial role. Our group has been at the forefront of research concerning the role of SO and PN in pain, and our current findings have led to the development of two new classes of orally active catalysts which are selective for PN decomposition while sparing SO. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.► A clear need exists for new, efficacious analgesics that lack risky side effects. ► Superoxide and peroxynitrite are key players in the development/maintenance of pain. ► Strategies targeting these species provide a promising therapy for pain management.
Keywords: Superoxide; Peroxynitrite; Pain; Nociception; Central sensitization;

While numerous lines of evidence point to increased levels of oxidative stress playing a causal role in a number of neurodegenerative conditions, our current understanding of the specific role of oxidative stress in the genesis and/or propagation of neurodegenerative diseases remains poorly defined. Even more challenging to the “oxidative stress theory of neurodegeneration” is the fact that many antioxidant-based clinical trials and therapeutic interventions have been largely disappointing in their therapeutic benefit. Together, these factors have led researchers to begin to focus on understanding the contribution of highly localized structures, and defined anatomical features, within the brain as the sites responsible for oxidative stress-induced neurodegeneration. This review focuses on the potential for oxidative stress within the cerebrovascular architecture serving as a modulator of neurodegeneration in a variety of pathological settings. In particular, this review highlights important implications for vascular-derived oxidative stress in the initiating and promoting pathophysiology in the brain, identifying new roles for cerebrovascular oxidative stress in a variety of brain disorders. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.► Review of the role of oxidative stress in neurodegenerative disease. ► Sources of cerebral endothelial cell oxidative stress are discussed. ► Effects of oxidative stress on cerebral endothelial cells are discussed. ► Some of the current antioxidant treatments are reviewed (pharmaceutical and dietary). ► The potential use of antioxidants targeted to cerebrovascular oxidative stress is discussed.
Keywords: Oxidative stress; Antioxidant; Cerebral endothelial cell; Neurodegeneration; Blood brain barrier; Vascularization;