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Logo of oximedOxidative Medicine and Cellular Longevity
Oxid Med Cell Longev. 2012; 2012: 163913.
Published online 2012 April 26. doi:  10.1155/2012/163913
PMCID: PMC3350994

The Bad, the Good, and the Ugly about Oxidative Stress


Alzheimer's disease (AD), Parkinson's disease (PD), and cancer (e.g., leukemia) are the most devastating disorders affecting millions of people worldwide. Except for some kind of cancers, no effective and/or definitive therapeutic treatment aimed to reduce or to retard the clinic and pathologic symptoms induced by AD and PD is presently available. Therefore, it is urgently needed to understand the molecular basis of these disorders. Since oxidative stress (OS) is an important etiologic factor of the pathologic process of AD, PD, and cancer, understanding how intracellular signaling pathways respond to OS will have a significant implication in the therapy of these diseases. Here, we propose a model of minimal completeness of cell death signaling induced by OS as a mechanistic explanation of neuronal and cancer cell demise. This mechanism might provide the basis for therapeutic design strategies. Finally, we will attempt to associate PD, cancer, and OS. This paper critically analyzes the evidence that support the “oxidative stress model” in neurodegeneration and cancer.

1. The Verdict: Oxygen Is Guilty, Not Guilty

Oxidative stress (OS) has become a major topic in all areas of medical knowledge. Entry of the term “oxidative stress” in PubMed ( shows that the number of publications has dramatically increased from none in the early 1970's to cover ~90,000 peer-reviewed articles in 2011 (Figure 1(a)). A similar trend is recorded for Alzheimer's disease (AD), Parkinson's disease (PD), and cancer when searched jointly with OS (Figure 1(b)). Since the discovery of the superoxide dismutase (SOD) in 1969 by McCord and Fridovich ([1], for a historical perspective see [24]), our understanding of the molecular defense mechanisms, which include catalase [5], glutathione peroxidase (GPx), and peroxiredoxin [6] and thioredoxin reductase [7], against diverse stress stimuli and pathogens [8] has dramatically changed (reviewed in [9, 10]). Moreover, given the phylogenetic distribution and subcellular localization of the SOD isozymes, the discovery has provided strong support for the hypothesis that the chloroplasts and mitochondria of eukaryotic cells arose from prokaryotic endosymbionts [11]. SOD is an enzyme that catalyzes the dismutation of the superoxide radical (O2·−) very efficiently (k2~2 × 109 M−1 s−1) through a redox reaction of its copper centre enzyme into oxygen (O2) and hydrogen peroxide (H2O2). Today, it is clear that decrease of enzymatic activity of the defense system or an overwhelming production of O2·− and/or H2O2 is linked to neurodegenerative disorders (e.g., familial amyotrophic lateral sclerosis [12], AD [13], PD [14], and cancer [15]). The idea that oxygen might not only be involved in the beginning of life and evolution [1618] but also it might be a toxic molecule [19] was further popularized by Halliwell and Gutteridge in their book entitled “Free Radicals in Biology and Medicine” [20] and some important follow-up papers [2123]. The chemistry of oxygen is well known. Basically, O2 is classified as a free radical. By definition, a free radical is an atom or group of atoms with at least one unpaired electron. Indeed, the electronic configuration of the oxygen diatom is [2He4]2s42p8 with the first ten electrons placed into σ, σ*, π, orbitals, and two unpaired electrons each located in a different π* antibonding orbital. Removal of an electron from O2 results in a superoxide cation radical (O2·+). In contrast, if a single electron is added, the product is the superoxide anion radical (O2·−). Addition of one more electron will yield the peroxide ion, O22−, which is not a radical. Since this reaction may take place in solution, it is quite likely that this ion became protonate (2H+) and converted into H2O2. This last compound represents a potential danger. In the presence of metal ions such as iron (Fe2+) and copper (Cu+), H2O2 decomposes into more reactive free radical specie, the hydroxyl radical (·OH). In sharp contrast with O2·−, there is not an antioxidant system to protect cells against ·OH. Indeed, this last radical can provoke a whole series of radical chain reactions involving damage of lipids, proteins, and nucleic acids. Therefore, an excessive generation or accumulation of O2·−/H2O2 may lead to a biochemical phenomenon known as OS. Simply, this term refers to an atypical state in which exaggerate production of reactive species overwhelms the antioxidant defense systems of the cell [24]. Interestingly, O2·− and H2O2 are recognized to play signaling functions (reviewed in [25, 26]). However, H2O2 best fulfills the requirements of being a second messenger, that is, its enzymatic production, along with the requirements for the oxidation of thiols by this molecule, provides the specificity for time and place that are required in signaling, whilst O2·− is more likely as a precursor of H2O2. Although efforts have been made to explain the complexities of OS in cancer [27, 28] and neurodegeneration [2931], several questions still remain unanswered, mainly because of two key issues. First, except for a few causative genetic mutations, the underlying pathogenic mechanism(s) of Parkinson's and Alzheimer's cases is not yet well understood. Consequently, this makes it difficult to identify potential therapeutic targets to stop their progression. Therefore, it is imperative to elucidate the precise molecular mechanism and/or identify the molecular “switches” that trigger neuronal death [32]. Clearly, identifying the precise steps/“switches” in the pathological cascade has been proven difficult since multiple death signaling pathways are often activated in response to a single stimulus. Thus, the questions what kills neurons and how do they get deteriorate in neurodegenerative diseases [33, 34] are still unresolved. Second, it is not surprising that some neuroprotective clinical trials had been completely unsatisfactory [3538]. This last outcome is even aggravated by either technical incongruities [39], the challenging task of recruitment and retention of subjects in clinical trials (e.g., AD, [40]), limited knowledge on antioxidant bioavailability [41, 42], or that they have failed because they have not been aimed at the right target [4345].

Figure 1
Number of articles reported in PubMed by using the term “oxidative stress” (OS) alone (a) or together (b) with the term “Parkinson” (P), “Alzheimer” (A), and “cancer”.

2. The Bad Touch of Oxidative Stress: Involvement in Alzheimer's and Parkinson's Disease

AD and PD are the two most common progressive neurodegenerative disorders worldwide [46, 47] affecting all ethnicities but especially some genetically isolated groups, such as the “paisa community” living in the Antioquia region of Colombia [4852]. AD and PD are neuropathologically characterized by abundant insoluble protein deposits (e.g., Aβ[1–40/42] and hyperphosphorylated tau in AD [53], α-Synuclein in PD [54], metal deposition (e.g., iron [5557]), specific neuronal and synaptic loss of the hippocampal pyramidal neurons (AD), and dopaminergic neurons of the substantia nigra (PD), probably via OS [58]. Despite the fact that both of these types of cells are vulnerable to OS, it is still unknown the complete cascade of molecular events at a single cell level responsible for neural deterioration. Consequently, no effective and/or definitive therapeutic treatment aimed at reducing or delaying clinical and pathological symptoms is currently available. Therefore, it is urgently needed to elucidate the molecular cell death signaling pathway involved in these processes to identify potential pharmacological target(s).

To get insight into these issues, we initially selected peripheral blood lymphocyte (PBL) culture as model system in AD and PD. Indeed, these cells display striking biochemical similarities to neurons (e.g., [5963]). Lymphocytes therefore represent a remarkable nonneural cell model for understanding the molecular machinery and metabolic regulation of apoptosis associated with cell survival signaling against stressful stimuli. Apoptosis is a controlled and regulated form of programmed cell death defined by specific morphological features such as rounding-up of the cell, reduction of cellular volume, chromatin condensation (i.e., stage I nuclei morphology composed of high molecular weight DNA), nuclear fragmentation (i.e., stage II nuclei morphology composed of low molecular weight DNA, highly chromatin condensation packed in round masses), classically little or no ultrastructural modifications of cytoplasmic organelles, and plasma membrane blebbing [64]. Although morphologically similar, apoptosis can be triggered through different intrinsic or extrinsic signaling biochemical routes [6567]. Because H2O2 is more stable reactive oxygen specie (ROS), it can work either as a second messenger in prosurvival [68] or in prodeath intracellular signaling pathways. During the last decade, we have focused on investigating the H2O2-induced cell death signaling in PBLs. We have consistently shown that Aβ[25–35] [69], dopamine (DA, [70]), and its related neurotoxins (e.g., 6-hydroxidopamine (6OHDA), 5,6 and 5,7-dyhydroxy-tryptamine (5,6- and -5,7-DHT, [71]), paraquat (PQ, [72]), and rotenone (ROT, [73]) induce apoptosis in lymphocytes in a concentration- and time-dependent fashion by OS mechanism involving several steps: O2·− and H2O2 generation (Figure 2, step 1, numbers in red), activation of the nuclear factor kappa-B (NF-κB, step 2)/p53 (step 3)/c-Jun N-terminal kinase (JNK, step 4)/c-Jun (step 5) transcription factors, mitochondrial depolarization (step 6), and caspase-3 activation (step 7). As a result we observed the typical nuclei morphological feature of apoptosis including chromatin condensation and fragmentation (step 8). Remarkably, this cell death subroutine can be blocked by the action of antioxidants (e.g., N-acetyl-cysteine (NAC) [69, 71], vitamin C (VC, [71]), testosterone [70], 17β-estradiol [70, 74], cannabinoids (e.g., CP55940 and JWH-015 [72, 75]), mitochondria permeabilization transition pore inhibitor (e.g., cannabinoids [76]), insulin-like growth factor-1 [72, 73, 77]), high glucose [72, 73], specific pharmacological inhibitors (e.g., PDTC, pifithrin-α, SP600125, Ac-DEVD-cho inhibitor of NF-κB, p53, JNK, and caspase-3, resp.) and inhibitors of protein (e.g., cycloheximide [71]), and RNA (e.g., actinomycin D [69, 71]) synthesis. These findings may be explained by the following assumptions. H2O2 might indirectly activate NF-κB through phosphorylation of the IκBα (i.e., the inhibitor of the complex NF-κB or p50/p62) either by the spleen tyrosine kinase protein (Syk, step 9, number in blue) at tyrosine 42 [78, 79] or at serine 32 and 36 via SH2 (Src homology 2)-containing inositol phosphatase-1 (SHIP-1, step 10)/IκB-kinase (IKK) complex pathway [80]. Alternatively, H2O2 might activate NF-κB through activation of the IKK complex by mitogen-activated protein kinase/ERK kinase kinase-1 (MEKK1, step 11, [81]). Once the IκB is phosphorylated, the release of active NF-κB dimmer (p50/p63) translocates into the nucleus and transcribes several antiapoptotic genes (e.g., Bcl-2, cIAP-1-2, and Bcl-xL) (step 12) and pro-apoptotic genes, amongst them the p53 [82]. At this point, a vicious cycle is established wherein p53 plays a critical role by balancing the cell to a death decision because of its many actions. First, p53 transcribes proapoptotic genes such as Bax (step 13), which in turn might contribute to the permeabilization of the outer mitochondrial membrane by antagonizing antiapoptotic proteins (e.g., Bcl-2, cIAP-1-2, and Bcl-xL). Second, p53 not only induces prooxidant genes (e.g., p53-induced gene-3 (PIG3), proline oxidase (PO), step 14), which generate more H2O2 but also represses the transcription of antioxidant genes (e.g., NAD(P)H: quinone oxidoreductase-1) [83]. Elevated stress stimuli (i.e., H2O2 production, step 1) and further activation of NF-κB induce upregulation of proapoptotic genes (e.g., p53), which in turn amplify the initial H2O2-induced cell death signal. Formation of the mitochondrial permeabilization transition pore allows the release of apoptogenic proteins (by a not fully established mechanism, step 15 [84, 85]) such as the apoptosis-inducer factor (AIF, [86]) responsible for causing DNA fragmentation and chromatin condensation (i.e., stage I nuclei morphology) and cytochrome C, which together with Apaf 1, dATP, and procaspase-9 (i.e., the apoptosome) elicits caspase-3 protease activation [87]. This protease is essential for the fragmentation and morphological changes associated with apoptosis [88]. Indeed, caspase-3 activates the endonuclease DNA fragmentation factor 40 (DFF40) or caspase-activated DNAse (CAD) by cutting the nuclease's inhibitor DFF45/ICAD [89]. Finally, DFF40/CAD causes nuclear chromatin fragmentation (i.e., stage II nuclei morphology), typical of apoptosis [90]. Interestingly, the apoptosis signal-regulating kinase (ASK1; step 16, [91]) and MEKK1 (step 11, [92]) phosphorylate MKK4/MAPK kinase (step 17). MEKK1 kinase therefore represents a cross-talk between the JNK and NF-κB pathway. Indeed, MEKK1 kinase phosphorylates IKK and MKK4. This last kinase phosphorylates JNK/stress apoptosis protein kinase (SAPK [93], step 4), which in turn phosphorylates the c-Jun transcription factor [94], also involved in transcription of death signaling [95]. Interestingly, it has also been shown that JNK1/2 cooperates in the activation of p53 apoptotic pathway [96, step 3]. Alternatively, high concentration of metal ions (e.g., Fe2+; Cu+, Mn2+) alone or in combination with H2O2 are able to directly induce mitochondria damage and apoptotic morphology by caspase-3-dependent mechanism [70, 97]. In conclusion, NF-κB, p53, c-Jun and caspase-3 activation, and mitochondrial depolarization are crucial events in mediating cell death by apoptosis.

Figure 2
Proposed model of minimal completeness of cell death signaling induced by oxidative stress as a mechanistic explanation of neuronal and cancer cell demise.The neurotoxins Aβ[25–35], dopamine (DA) and its related neurotoxins (6OHDA, 5,6- ...

Over the years, not only in vitro (e.g., [98107] or in situ (e.g., [55, 108115]) but also in vivo studies have validated the findings highlighted in Figure 2, step 1–8. Of note, McLellan et al. [116] have shown directly that a subset of amyloid plaques (e.g., dense core plaques) produce ROS, that is, H2O2, in animal Alzheimer's models (e.g., Tg2576 APP overexpressing transgenic mice) and in human postmortem Alzheimer tissue. Wang et al. [117] found that Aβ[1–42] injection in Sprague-Dawley male rats increased JNK and NF-κB protein levels in brain. This effect was prevented by hydrogen-rich saline implicating OS. Likewise, Mogi et al. [118, 119] showed significant increase in the levels of p53, NF-κB, and caspase-3 reflecting apoptosis in the Parkinsonian brain. In agreement with these human brain data, Liang et al. [120] have shown that NF-κB activation contributes to 6-OHDA OS-induced degeneration of dopaminergic neurons through a NF-κB-dependent p53-signaling pathway in rat model of PD. Interestingly, Li et al. [121] have shown that bilobalide (an active component of Gingko biloba) and the peptide inhibitor of NF-κB, SN50 inhibit 6-OHDA-induced activation of NF-κB and loss of dopaminergic neurons in rat substantia nigra. Muñoz et al. [122] have shown that systemic administration of NAC protects dopaminergic neurons against 6-OHDA-induced degeneration in rats. Remarkably, Braithwaite et al. [123] have shown that SP600125 inhibition of JNK provides neuroprotection in a Tg2576/PSm146L transgenic mice model of AD. To establish in vivo relevance of our in vitro findings, we showed that SP600125 increased the survival and locomotor activity of Drosophila melanogaster (D. melanogaster [124]), used as a valid model of PD [125, 126], against acute exposure to PQ [127]. Furthermore, the cannabinoid CP55,940 prolongs survival and improves locomotor activity in Drosophila against acute exposure to PQ [124]. We also demonstrated that pure polyphenols such as gallic acid (GA), ferulic acid (FA), caffeic acid (CA), coumaric acid (CouA), propyl gallate (PG), epicatechin (EC), epigallocatechin (EGC), and epigallocatechin gallate (EGCG) protect, rescue, and, most importantly, restore the impaired movement activity (i.e., climbing capability) induced by PQ in the fly [128]. Remarkably, PG and EGCG protected and maintained movement abilities in flies cotreated with PQ and iron [128]. Recently, Ortega-Arellano et al. [129] have demonstrated that chronic polyphenols prolong life span and restore locomotor activity of D. melanogaster chronically exposed to PQ compared to flies treated with PQ alone. These observations support the notion that polyphenols might be potential therapeutic compounds in the treatment of PD [130, 131]. Moreover, Bonilla-Ramirez et al., [132] have found that desferrioxamine (DFO), ethylenediaminetetraacetic acid (EGTA), and D-penicillamine chelators were able to protect but not rescue D. melanogaster against acute or chronic metal intoxication. Taken together, in vitro and in vivo data suggest that antioxidants (e.g., NAC [133]), polyphenols, cannabinoids, metal chelators [134], mitochondrial targeted antioxidant compounds [135, 136], pharmacological inhibition of NF-κB [137, 138], p53 [139, 140], JNK [141], and caspase-3 may be of therapeutic value in AD and PD.

3. The Good Touch of Oxidative Stress: A Perspective for Cancer Cell Death

Oxidative stress has two opposite outcomes in cancer cells: on one side, OS has been associated to initiation, promotion, progression, and maintenance of tumor cell phenotypes [26, 27]. Specifically, H2O2 stimulates proliferation, migration, and adhesion of these cells [142144]. However, the causative relationship of ROS increase, and oncogene activation remains unclear. On the other side, OS has been associated with antitumorigenic actions, senescence, and apoptosis [145, 146]. Strikingly, NF-κB has been found to play pro- and antiapoptotic roles, which might depend on the type of cell [147151], intracellular level of ROS, induced or constitutive expression of NF-κB, quantity of cellular antioxidant defenses, and absence or presence of growth factors or metabolic sources (e.g., glucose). Therefore, NF-κB constitutes a critical molecule in cell survival/death decision. Based on our previous experience with OS mechanism and cell death, we hypothesize that cancer and neurodegeneration processes share common cellular foundations. In contrast to the unsatisfactory results of the antioxidant therapy in AD [152, 153] and PD [154], generation of ROS to kill cancer cells is currently not only an idea but has already been effective as treatment in cancer patients (e.g., procarbazine, doxorubicin, and arsenic). We reasoned that the OS mechanism depicted in the Figure 2 might be operative in both neurodegeneration and cancer processes but with opposite therapeutic approaches: while it might be used to destroy malignant cells, it might also be stopped with antioxidants or signals to retard or delay neural cell death. Concerning the former consideration, we found that low-dose (10 μM) vitamin K3 (VK3, also known as menadione or 2-Methyl-1,4-naphthoquinone) or high-dose (10 mM) vitamin C (VC, also known as ascorbate, AscH) alone or in combination induced apoptosis in Jurkat (model of acute lymphoblastic T-cell leukemia [155]) and K562 (model of myelogenous leukaemia cells) cells by OS mechanism [156]. This data provided, for the first time, in vitro evidence supporting a causative role for OS in VK3- and VC-induced apoptosis in Jurkat and K562 cells in a domino-like mechanism similar to the mechanism identified in lymphocytes and neuronal cells under OS (Figure 2). The VC/VK3 observations can be explained because the synthetic VK3 can be reduced via one- or two-electron transfer by intracellular reductases or by VC. The two electron reductions of VK3 to hydroquinone VK3 (VK3QH2) can slowly autoxidise to reform VK3. The single-electron reduction of the VK3 by VC (AscH) gives semiquinone anion radical (VK3Q·−), which in turn reduces O2 to O2·− and regenerates the VK3. Consequently, redox cycling of VK3 can ensue and produce large amounts of O2·−, which can dismutate via SOD to form H2O2 and O2. As mentioned, H2O2 can take part in metal-catalyzed reactions to form more toxic species of active oxygen such as ·OH. Therefore, if the single-electron reduction pathway predominates and the rate of redox cycling of VK3 exceeds the capacity of the detoxifying enzymes (e.g., catalase, GPx, and SOD), OS occurs, ultimately triggering a specific subroutine of cell death signaling (Figure 2 and [156]). Altogether these data suggest that VK3 and VC or any molecule capable of producing excessive amount of O2·−/H2O2 can be useful in the treatment of leukemia (e.g., arsenic [157], taxol [158]).

4. Dangerous Liaisons: Oxidative Stress as Central Aspect for Neurodegeneration and Cancer

Up-to-date, >200 pathogenic mutations distributed in 3 (Aβ amyloid precursor protein (APP), presenilin-1 (PSEN1), presenilin-2 (PSEN2)), and 6 genes (α-Synuclein (SNCA), Leucine-rich repeat kinase 2 (LRRK2), PARKIN, PTEN-induced putative kinase 1 (PINK1), DJ-1, and P-type ATPase 13A2 (ATP13A2)) have been conclusively shown to cause familial Alzheimer and Parkinsonism, respectively (, reviewed in [159, 160]). Interestingly, mutations in those genes are directly related to OS and mitochondrial alterations [161, 162]. Specifically, Vinish et al. [163] have found increase in malondialdehyde content and SOD activity in peripheral blood parameters in PD patients with PARKIN mutations in comparison to controls. Ramsey and Giasson [164] found that the p.E163K DJ-1 mutant loses the ability to protect against OS while demonstrating a reduced redistribution towards mitochondria. Moreover, Ren et al. [165] have shown that DJ-1 protects cells against UVB-induced cell death dependent on its oxidation and its association with mitochondrial Bcl-X(L). Heo et al. [166] have shown that the p.G2019S mutation in LRRK2 generates H2O2 and induces neurotoxicity via its kinase activity. Last, the Butterfield's group has shown that mutation in APP and PSEN1 (e.g., APPNLH/PS-1P264L mice) induces brain OS [167, 168]. Taken together, these data support the notion that environmental and genetic pathways converge in the pathogenesis of AD [169] and PD [170172]. It is interesting to note that iron accumulation is linked with the brain pathology in AD [55] and familial PD [56, 57]. These observations suggest that iron might play a toxic role in the pathophysiology of both neurologic disorders [173, 174], most probably linked to a common molecular mechanism of cell death via generation of intermediate ROS and mitochondrial damage [97, 175, 176]. Therefore, it is not unusual that PD patients develop dementia [164, 177, 178] concomitantly with AD pathology [179]. Moreover, recent data suggest that exposition to ethacrynic acid, a compound that induces cellular glutathione (GSH) depletion therefore causing OS, increases presenilin-1 protein levels in human neuroblastoma SH-SY5Y cells [180]. Furthermore, the γ-secretase protein complex mediates OS-induced expression of β-site APP cleaving enzyme I (BACE1) resulting in excessive Aβ production in AD [181]. Remarkably, extensive analysis of the effects and interactions of the AD [182, 183] and PD [184, 185] pathogenic genes in D. melanogaster has shown that mutations in parkin [186, 187], pink-1 [188], α-synuclein [189], Lrrk [190] genes, or overexpression of normal α-synuclein [189] cause death of dopaminergic neurons in Drosophila probably via OS [166, 191195]. Accordingly, it has been shown that DJ-1 and parkin are essential for mitochondrial function and rescue pink-1 loss of function [196, 197]. Since these genes are conserved in invertebrates (insects) and vertebrates (mammals) [198], we believe that D. melanogaster could provide new insights into the relationship between gene mutations, OS, and mitochondria [184]. Taken together, these data suggest that OS is at the pathobiological basis of PD and AD and that its generation and detrimental effects can be exacerbated by environmental factors and mutation in causative genes.

Surprisingly, epidemiological studies have consistently shown the cooccurrence of PD and melanoma [199, 200] and this association is strongly increased by mutations in PARKIN, LRRK2, and α-Synuclein (for a review, see [201]). Moreover, Veeriah et al. [202] have shown that point mutations and exon rearrangements of PARKIN are linked to glioblastoma multiform, colon cancer, and lung cancer. Although, the exact mechanism(s) underlying the observed cancer-PD association is not clear, it has been suggested that genes (e.g., PARKIN) that cause neuronal dysfunction when mutated in the germline may instead contribute to oncogenesis when altered in nonneuronal somatic cells [202]. Whether OS is involved in these malignancies needs further investigation. However, based on the assumption that cancer and neurodegeneration share some of the same genes and molecular mechanisms of OS-induced cell death, one may anticipate a positive correlation between OS, cancer and PD. Recently, Zhang et al. [203] have found that Parkin is a p53 target and Parkin contributes to the role of p53 in regulating antioxidant defense. Indeed, ectopic Parkin expression significantly reduced ROS levels in H460p53siRNA treated with or without H2O2. Simultaneous knockdown of p53 and Parkin results in higher intracellular ROS levels than individual knockdown of p53 and Parkin. Moreover, ectopic Parkin expression significantly increased GSH (reduced) levels, thus altering the GSH : GSSG (oxidized) ratio in human lung cancer line, H460p53siRNA. Interestingly, Parkin knockdown in H460 (control) cells and Parkin knockout in mouse embryonic fibroblast (MEF) cells significantly decreased GSH levels and the GSH : GSSG ratio. Given that Parkin has also been reported to repress p53 [204], together these data suggest that the regulation of Parkin by p53, or vice versa, could be cell type or tissue specific. Further investigation is warranted in this topic.

5. Oxidative Stress: Quo Vadis?

In conclusion, there is enough support evidence for the role of OS in AD, PD, and cancer. Clearly, the relationships between some causative genes of Parkinson's such as PARKIN and LRRK2 and cancer will challenge the medical research for designing new therapeutic approaches and the necessity to bring new proposals of unified models of disease and molecular mechanisms. In this respect, the model of minimal completeness of cell death induced by H2O2 (see Figure 2, steps 2–8) might provide a platform to evaluate new natural or synthetic antioxidants, pharmacological agents which target the mitochondria, transcription factor(s), and/or caspase-3, or it simply might be used as a model to test other novel hypothesis (e.g., [205, 206]). In this regard, plant polyphenols has been suggested as promising compounds for the prevention of neurodegenerative diseases and treatment of cancer (For reviews see [130, 207209]). Yet, whether polyphenols might function as effective antioxidant compounds in vivo is still a controversial issue [210213]. One of the most urgent issues is to clarify the many studies reported to show failed clinical benefit or persuasive evidence of neuroprotection [214]. Most importantly, we will need to definitely establish the molecular mechanism(s) of cell death in neurodegenerative disorders before novel treatments can be available. Undoubtedly, there are still many unresolved issues. Perhaps, studying the biology of cancer cells might provide understanding of the underlying pathogenic mechanisms of cell death in neurodegeneration and help developing new treatment strategies.


The work was supported by Colciencias (Grant #111534319119, 111540820504, and 111540820525) and UdeA (Grant #8780).


1. McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein) Journal of Biological Chemistry. 1969;244(22):6049–6055. [PubMed]
2. McCord JM, Fridovich I. Superoxide dismutase: the first twenty years (1968–1988) Free Radical Biology and Medicine. 1988;5(5-6):363–369. [PubMed]
3. Fridovich I. With the help of giants. Annual Review of Biochemistry. 2003;72:1–18. [PubMed]
4. Kresge N, Simoni RD, Hill RL. Forty years of superoxide dismutase research: the work of Irwin Fridovich. The Journal of Biological Chemistry. 2006;281:e17–e19.
5. Goyal MM, Basak A. Human catalase: looking for complete identity. Protein and Cell. 2010;1(10):888–897. [PMC free article] [PubMed]
6. Flohé L, Toppo S, Cozza G, Ursini F. A comparison of thiol peroxidase mechanisms. Antioxidants and Redox Signaling. 2011;15(3):763–780. [PubMed]
7. Holmgren A, Lu J. Thioredoxin and thioredoxin reductase: current research with special reference to human disease. Biochemical and Biophysical Research Communications. 2010;396(1):120–124. [PubMed]
8. Leto TL, Geiszt M. Role of Nox family NADPH oxidases in host defense. Antioxidants and Redox Signaling. 2006;8(9-10):1549–1561. [PubMed]
9. D'alessandro A, Zolla L. The SODyssey: superoxide dismutases from biochemistry, through proteomics, to oxidative stress, aging and nutraceuticals. Expert Review of Proteomics. 2011;8(3):405–421. [PubMed]
10. Batinić-Haberle I, Rebouças JS, Spasojević I. Superoxide dismutase mimics: chemistry, pharmacology, and therapeutic potential. Antioxidants and Redox Signaling. 2010;13(6):877–918. [PMC free article] [PubMed]
11. Grace SC. Phylogenetic distribution of superoxide dismutase supports an endosymbiotic origin for chloroplasts and mitochondria. Life Sciences. 1990;47(21):1875–1886. [PubMed]
12. Aksoy H, Dean G, Elian M, et al. A4T mutation in the SOD1 gene causing familial amyotrophic lateral sclerosis. Neuroepidemiology. 2003;22(4):235–238. [PubMed]
13. Calabrese V, Sultana R, Scapagnini G, et al. Nitrosative stress, cellular stress response, and thiol homeostasis in patients with Alzheimer’s disease. Antioxidants and Redox Signaling. 2006;8(11-12):1975–1986. [PubMed]
14. Martin HL, Teismann P. Glutathione - A review on its role and significance in Parkinson’s disease. FASEB Journal. 2009;23(10):3263–3272. [PubMed]
15. Popov B, Gadjeva V, Valkanov P, Popova S, Tolekova A. Lipid peroxidation, superoxide dismutase and catalase activities in brain tumor tissues. Archives of Physiology and Biochemistry. 2003;111(5):455–459. [PubMed]
16. Kerr RA. Earth science. The story of O2. Science. 2005;308(5729):1730–1732. [PubMed]
17. Kerr RA. Geochemistry. A shot of oxygen to unleash the evolution of animals. Science. 2006;314(5805):p. 1529. [PubMed]
18. Falkowski PG, Isozaki Y. Geology: the story of O2. Science. 2008;322(5901):540–542. [PubMed]
19. Fridovich I. Oxygen toxicity: a radical explanation. Journal of Experimental Biology. 1998;201(8):1203–1209. [PubMed]
20. Halliwel B, Gutteridge JMC. Free Radicals in Biology and Medicine. New York, NY, USA: Oxford University Press; 1985.
21. Halliwell B. Tell me about free radicals, doctor: a review. Journal of the Royal Society of Medicine. 1989;82(12):747–752. [PMC free article] [PubMed]
22. Halliwell B. Reactive species and antioxidants. Redox biology is a fundamental theme of aerobic life. Plant Physiology. 2006;141(2):312–322. [PubMed]
23. Halliwell B. Biochemistry of oxidative stress. Biochemical Society Transactions. 2007;35(5):1147–1150. [PubMed]
24. Halliwell B, Whiteman M. Measuring reactive species and oxidative damage in vivo and in cell culture: how should you do it and what do the results mean? British Journal of Pharmacology. 2004;142(2):231–255. [PMC free article] [PubMed]
25. Forman HJ, Maiorino M, Ursini F. Signaling functions of reactive oxygen species. Biochemistry. 2010;49(5):835–842. [PMC free article] [PubMed]
26. Brigelius-Flohé R, Flohé L. Basic principles and emerging concepts in the redox control of transcription factors. Antioxidants and Redox Signaling. 2011;15(8):2335–2381. [PMC free article] [PubMed]
27. Halliwell B. Oxidative stress and cancer: have we moved forward? Biochemical Journal. 2007;401(1):1–11. [PubMed]
28. Visconti R, Grieco D. New insights on oxidative stress in cancer. Current Opinion in Drug Discovery and Development. 2009;12(2):240–245. [PubMed]
29. Halliwell B. Oxidative stress and neurodegeneration: where are we now? Journal of Neurochemistry. 2006;97(6):1634–1658. [PubMed]
30. Reynolds A, Laurie C, Lee Mosley R, Gendelman HE. Oxidative stress and the pathogenesis of neurodegenerative disorders. International Review of Neurobiology. 2007;82:297–325. [PubMed]
31. Ikawa M, Okazawa H, Kudo T, Kuriyama M, Fujibayashi Y, Yoneda M. Evaluation of striatal oxidative stress in patients with Parkinson's disease using [ 62Cu]ATSM PET. Nuclear Medicine and Biology. 2011;38(7):945–951. [PubMed]
32. Golde TE. The therapeutic importance of understanding mechanisms of neuronal cell death in neurodegenerative disease. Molecular Neurodegeneration. 2009;4(1, article no. 8) [PMC free article] [PubMed]
33. Golde TE, Petrucelli L. "What kills neurons in neurodegenerative diseases?", A review series in an open access journal. Molecular Neurodegeneration. 2009;4(1, article no. 7) [PMC free article] [PubMed]
34. Surmeier DJ, Guzman JN, Sanchez-Padilla J, Goldberg JA. What causes the death of dopaminergic neurons in Parkinson’s disease? Progress in Brain Research. 2010;183(C):59–77. [PubMed]
35. Olanow CW, Kieburtz K, Schapira AHV. Why have we failed to achieve neuroprotection in Parkinson’s disease? Annals of Neurology. 2008;64, supplement 2:S101–S110. [PubMed]
36. Rafii MS, Aisen PS. Recent developments in Alzheimer’s disease therapeutics. BMC Medicine. 2009;7, article no. 7
37. Löhle M, Reichmann H. Clinical neuroprotection in Parkinson’s disease—still waiting for the breakthrough. Journal of the Neurological Sciences. 2010;289(1-2):104–114. [PubMed]
38. Lauterbach EC, Victoroff J, Coburn KL, Shillcutt SD, Doonan SM, Mendez MF. Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data. Journal of Neuropsychiatry and Clinical Neurosciences. 2010;22(1):8–18. [PubMed]
39. Frankel EN, Finley JW. How to standardize the multiplicity of methods to evaluate natural antioxidants. Journal of Agricultural and Food Chemistry. 2008;56(13):4901–4908. [PubMed]
40. Knebl JA, Patki D. Recruitment of subjects into clinical trials for Alzheimer disease. Journal of the American Osteopathic Association. 2010;110(9, supplement 8):S43–S49. [PubMed]
41. Singh M, Arseneault M, Sanderson T, Murthy V, Ramassamy C. Challenges for research on polyphenols from foods in Alzheimer’s disease: bioavailability, metabolism, and cellular and molecular mechanisms. Journal of Agricultural and Food Chemistry. 2008;56(13):4855–4873. [PubMed]
42. D’Archivio M, Filesi C, Varì R, Scazzocchio B, Masella R. Bioavailability of the polyphenols: status and controversies. International Journal of Molecular Sciences. 2010;11(4):1321–1342. [PMC free article] [PubMed]
43. Stevenson DE, Hurst RD. Polyphenolic phytochemicals - Just antioxidants or much more? Cellular and Molecular Life Sciences. 2007;64(22):2900–2916. [PubMed]
44. Standaert DG, Yacoubian TA. Target validation: the Parkinson disease perspective. DMM Disease Models and Mechanisms. 2010;3(5-6):259–262. [PubMed]
45. Liu Y, Schubert DR. The specificity of neuroprotection by antioxidants. Journal of Biomedical Science. 2009;16(1, article no. 98)
46. Alzheimer's Association, Thies W, Bleiler L. 2011 Alzheimer's disease facts and figures. Alzheimer's and Dementia. 2011;7(2):208–244. [PubMed]
47. Wirdefeldt K, Adami H-O, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson's disease: a review of the evidence. European Journal of Epidemiology. 2011;26, supplement 1:S1–S58. [PubMed]
48. Lopera F, Ardilla A, Martínez A, et al. Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. Journal of the American Medical Association. 1997;277(10):793–799. [PubMed]
49. Pineda-Trujillo N, Carvajal-Carmona LG, Buriticá O, et al. A novel Cys212Tyr founder mutation in parkin and allelic heterogeneity of juvenile Parkinsonism in a population from North West Colombia. Neuroscience Letters. 2001;298(2):87–90. [PubMed]
50. Pineda-Trujillo N, Apergi M, Moreno S, et al. A genetic cluster of early onset Parkinson’s disease in a Colombian population. American Journal of Medical Genetics, Part B. 2006;141(8):885–889. [PubMed]
51. Pineda-Trujillo N, Cepeda AD, Pérez WA, et al. Una mutación en el gen PARK2 causa enfermedad de Parkinson juvenil en una extensa familia colombiana. Iatreia. 2009;22(2):122–131.
52. Barral F. Doctors explain battle to beat Alzheimer's. CNN, January, 2011,
53. Esiri MM. The neuropathology of Alzheimer’s disease. In: Dawbarn D, Allen SJ, editors. Neurobiology of Alzheimer’s disease. Oxford, UK: Oxford University Press; 2007. pp. 37–58.
54. Forno LS. Neuropathology of Parkinson’s disease. Journal of Neuropathology and Experimental Neurology. 1996;55(3):259–272. [PubMed]
55. Smith MA, Harris PLR, Sayre LM, Perry G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proceedings of the National Academy of Sciences of the United States of America. 1997;94(18):9866–9868. [PubMed]
56. Takanashi M, Mochizuki H, Yokomizo K, et al. Iron accumulation in the substantia nigra of autosomal recessive juvenile parkinsonism (ARJP) Parkinsonism and Related Disorders. 2001;7(4):311–314. [PubMed]
57. Schneider SA, Paisan-Ruiz C, Quinn NP, et al. ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation. Movement Disorders. 2010;25(8):979–984. [PubMed]
58. Wang X, Michaelis EK. Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci. 2010;2, article 12 [PMC free article] [PubMed]
59. Shinde S, Pasupathy K. Respiratory-chain enzyme activities in isolated mitochondria of lymphocytes from patients with Parkinson’s disease: preliminary study. Neurology India. 2006;54(4):390–393. [PubMed]
60. MacIver NJ, Jacobs SR, Wieman HL, Wofford JA, Coloff JL, Rathmell JC. Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival. Journal of Leukocyte Biology. 2008;84(4):949–957. [PubMed]
61. Calopa M, Bas J, Callén A, Mestre M. Apoptosis of peripheral blood lymphocytes in Parkinson patients. Neurobiology of Disease. 2010;38(1):1–7. [PubMed]
62. Marazziti D, Consoli G, Masala I, Catena Dell’Osso M, Baroni S. Latest advancements on serotonin and dopamine transporters in lymphocytes. Mini-Reviews in Medicinal Chemistry. 2010;10(1):32–40. [PubMed]
63. Feldhaus P, Fraga DB, Ghedim FV, et al. Evaluation of respiratory chain activity in lymphocytes of patients with Alzheimer disease. Metabolic Brain Disease. 2011;26(3):229–236. [PubMed]
64. Kroemer G, Galluzzi L, Vandenabeele P, et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death and Differentiation. 2009;16(1):3–11. [PMC free article] [PubMed]
65. Reed JC. Mechanisms of apoptosis. American Journal of Pathology. 2000;157(5):1415–1430. [PubMed]
66. KEGG. The (Kyoto Encyclopedia of Genes and Genomes) PATHWAY Database. (Apoptosis)
67. Galluzzi L, Vitale I, Abrams JM, et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death and Differentiation. 2012;19(1):107–120. [PMC free article] [PubMed]
68. Groeger G, Quiney C, Cotter TG. Hydrogen peroxide as a cell-survival signaling molecule. Antioxidants and Redox Signaling. 2009;11(11):2655–2671. [PubMed]
69. Velez-Pardo C, Garcia-Ospina G, Del Rio JM. Aβ[25–35] peptide and iron promote apoptosis in lymphocytes by a common oxidative mechanism: involvement of hydrogen peroxide (H2O2), caspase-3, NF-kappa B, p53 and c-Jun. NeuroToxicol. 2002;23(3):351–365. [PubMed]
70. Del Rio MJ, Moreno S, Garcia-Ospina G, et al. Autosomal recessive juvenile Parkinsonism Cys212Tyr mutation in parkin renders lymphocytes susceptible to dopamine- and iron-mediated apoptosis. Movement Disorders. 2004;19(3):324–330. [PubMed]
71. Del Rio MJ, Velez-Pardo C. Monoamine neurotoxins-induced apoptosis in lymphocytes by a common oxidative stress mechanism: Involvement of hydrogen peroxide (H2O2), caspase-3, and nuclear factor kappa-B (NF-κB), p53, c-Jun transcription factors. Biochemical Pharmacology. 2002;63(4):677–688. [PubMed]
72. Jimenez Del Rio M, Velez-Pardo C. Paraquat induces apoptosis in human lymphocytes: protective and rescue effects of glucose, cannabinoids and insulin-like growth factor-1. Growth Factors. 2008;26(1):49–60. [PubMed]
73. Avila-Gomez IC, Velez-Pardo C, Jimenez-Del-Rio M. Effects of insulin-like growth factor-1 on rotenone-induced apoptosis in human lymphocyte cells. Basic and Clinical Pharmacology and Toxicology. 2010;106(1):53–61. [PubMed]
74. Jimenez Del Rio M, Velez-Pardo C. 17β-Estradiol protects lymphocytes against dopamine and iron-induced apoptosis by a genomic-independent mechanism - Implication in Parkinson’s disease. General Pharmacology: The Vascular System. 2001;35(1):1–9. [PubMed]
75. Velez-Pardo C, Jimenez Del Rio M. Avoidance of Aβ[25-35]/(H2O2)-induced apoptosis in lymphocytes by the cannabinoid agonists CP55,940 and JWH-015 via receptor-independent and PI3K-dependent mechanism: role of NF-κB and p53. Medicinal Chemistry. 2006;2(5):471–479. [PubMed]
76. Velez-Pardo C, Jimenez-Del-Rio M, Lores-Arnaiz S, Bustamante J. Protective effects of the synthetic cannabinoids CP55,940 and JWH-015 on rat brain mitochondria upon paraquat exposure. Neurochemical Research. 2010;35(9):1323–1332. [PubMed]
77. Jimenez Del Rio M, Velez-Pardo C. Insulin-like growth factor-1 prevents Aβ[25–35]/ (H2O2)- induced apoptosis in lymphocytes by reciprocal NF-κB activation and p53 inhibition via PI3K-dependent pathway. Growth Factors. 2006;24(1):67–78. [PubMed]
78. Schoonbroodt S, Ferreira V, Best-Belpomme M, et al. Crucial role of the amino-terminal tyrosine residue 42 and the carboxylterminal PEST domain of I kappa B alpha in NF-kappa B activation by an oxidative stress. J Immunol. 2000;164(8):4292–4300. [PubMed]
79. Takada Y, Mukhopadhyay A, Kundu GC, Mahabeleshwar GH, Singh S, Aggarwal BB. Hydrogen peroxide activates NF-κB through tyrosine phosphorylation of IκBα and serine phosphorylation of p65. Evidence for the involvement of IκBα kinase and Syk protein-tyrosine kinase. Journal of Biological Chemistry. 2003;278(26):24233–24241. [PubMed]
80. Gloire G, Charlier E, Rahmouni S, et al. Restoration of SHIP-1 activity in human leukemic cells modifies NF-κB activation pathway and cellular survival upon oxidative stress. Oncogene. 2006;25(40):5485–5494. [PubMed]
81. Lee FS, Hagler J, Chen ZJ, Maniatis T. Activation of the IκBα kinase complex by MEKK1, a kinase of the JNK pathway. Cell. 1997;88(2):213–222. [PubMed]
82. Wu H, Lozano G. NF-κB activation of p53. A potential mechanism for suppressing cell growth in response to stress. Journal of Biological Chemistry. 1994;269(31):20067–20074. [PubMed]
83. Olovnikov IA, Kravchenko JE, Chumakov PM. Homeostatic functions of the p53 tumor suppressor: regulation of energy metabolism and antioxidant defense. Seminars in Cancer Biology. 2009;19(1):32–41. [PMC free article] [PubMed]
84. Borutaite V. Mitochondria as decision-makers in cell death. Environmental and Molecular Mutagenesis. 2010;51(5):406–416. [PubMed]
85. Ricchelli F, Šileikyte J, Bernardi P. Shedding light on the mitochondrial permeability transition. Biochimica et Biophysica Acta. 2011;1807(5):482–490. [PubMed]
86. Norberg E, Orrenius S, Zhivotovsky B. Mitochondrial regulation of cell death: processing of apoptosis-inducing factor (AIF) Biochemical and Biophysical Research Communications. 2010;396(1):95–100. [PubMed]
87. Zou H, Li Y, Liu X, Wang X. An APAf-1 · cytochrome C multimeric complex is a functional apoptosome that activates procaspase-9. Journal of Biological Chemistry. 1999;274(17):11549–11556. [PubMed]
88. Jänicke RU, Sprengart ML, Wati MR, Porter AG. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. Journal of Biological Chemistry. 1998;273(16):9357–9360. [PubMed]
89. Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature. 1998;391(6662):43–50. [PubMed]
90. Yuste VJ, Sánchez-López I, Solé C, et al. The contribution of apoptosis-inducing factor, caspase-activated DNase, and inhibitor of caspase-activated DNase to the nuclear phenotype and DNA degradation during apoptosis. Journal of Biological Chemistry. 2005;280(42):35670–35683. [PubMed]
91. Ichijo H, Nishida E, Irie K, et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 1997;275(5296):90–94. [PubMed]
92. Yan M, Dai T, Deak JC, et al. Activation of stress activated protein kinase by MEKK1 phosphorylation of its activator SEK1. Nature. 1994;372(6508):798–800. [PubMed]
93. Yang D, Tournier C, Wysk M, et al. Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity. Proceedings of the National Academy of Sciences of the United States of America. 1997;94(7):3004–3009. [PubMed]
94. Minden A, Lin A, Smeal T, et al. c-Jun N-terminal phosphorylation correlates with activation of the JNK subgroup but not the ERK subgroup of mitogen-activated protein kinases. Molecular and Cellular Biology. 1994;14(10):6683–6688. [PMC free article] [PubMed]
95. Dhanasekaran DN, Reddy EP. JNK signaling in apoptosis. Oncogene. 2008;27(48):6245–6251. [PMC free article] [PubMed]
96. Oleinik NV, Krupenko NI, Krupenko SA. Cooperation between JNK1 and JNK2 in activation of p53 apoptotic pathway. Oncogene. 2007;26(51):7222–7230. [PubMed]
97. Jiménez Del Río M, Vélez-Pardo C. Transition metal-induced apoptosis in lymphocytes via hydroxyl radical generation, mitochondria dysfunction, and caspase-3 activation: an in vitro model for neurodegeneration. Archives of Medical Research. 2004;35(3):185–193. [PubMed]
98. Bales KR, Du Y, Dodel RC, Yan GM, Hamilton-Byrd E, Paul SM. The NF-κB/Rel family of proteins mediates A β-induced neurotoxicity and glial activation. Molecular Brain Research. 1998;57(1):63–72. [PubMed]
99. Uberti D, Yavin E, Gil S, Ayasola KR, Goldfinger N, Rotter V. Hydrogen peroxide induces nuclear translocation of p53 and apoptosis in cells of oligodendroglia origin. Molecular Brain Research. 1999;65(2):167–175. [PubMed]
100. Marín N, Romero B, Bosch-Morell F, et al. β-Amyloid-induced activation of Caspase-3 in primary cultures of rat neurons. Mechanisms of Ageing and Development. 2000;119(1-2):63–67. [PubMed]
101. Panet H, Barzilai A, Daily D, Melamed E, Offen D. Activation of nuclear transcription factor kappa B (NF-κB) is essential for dopamine-induced apoptosis in PC12 cells. Journal of Neurochemistry. 2001;77(2):391–398. [PubMed]
102. Troy CM, Rabacchi SA, Xu Z, et al. β-Amyloid-induced neuronal apoptosis requires c-Jun N-terminal kinase activation. Journal of Neurochemistry. 2001;77(1):157–164. [PubMed]
103. Aleyasin H, Cregan SP, Iyirhiaro G, et al. Nuclear factor-κB modulates the p53 response in neurons exposed to DNA damage. Journal of Neuroscience. 2004;24(12):2963–2973. [PubMed]
104. Ohyagi Y, Asahara H, Chui DH, et al. Intracellular Aβ42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer’s disease. FASEB Journal. 2005;19(2):255–257. [PubMed]
105. Son Y-O, Jang YS, Shi X, Lee JC. Activation of JNK and c-Jun is involved in glucose oxidase-mediated cell death of human lymphoma cells. Molecules and Cells. 2009;28(6):545–551. [PubMed]
106. Choi WS, Klintworth HM, Xia Z. JNK3-mediated apoptotic cell death in primary dopaminergic neurons. Methods in Molecular Biology. 2011;758:279–292. [PMC free article] [PubMed]
107. Maheshwari A, Misro MM, Aggarwal A, Sharma RK, Nandan D. N-acetyl-L-cysteine counteracts oxidative stress and prevents H2O2 induced germ cell apoptosis through down-regulation of caspase-9 and JNK/c-Jun. Molecular Reproduction and Development. 2011;78(2):69–79. [PubMed]
108. Hunot S, Brugg B, Ricard D, et al. Nuclear translocation of NF-κb is increased in dopaminergic neurons of patients with Parkinson disease. Proceedings of the National Academy of Sciences of the United States of America. 1997;94(14):7531–7536. [PubMed]
109. He Y, Lee T, Leong SK. 6-Hydroxydopamine induced apoptosis of dopaminergic cells in the rat substantia nigra. Brain Research. 2000;858(1):163–166. [PubMed]
110. Hartmann A, Hunot S, Michel PP, et al. Caspase-3: a vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson’s disease. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(6):2875–2880. [PubMed]
111. Velez-Pardo C, Lopera F, Jimenez Del Rio M. DNA damage does not correlate with amyloid-β-plaques and neurofibrillary tangles in familial Alzheimer’s disease presenilin-1 [E280A] mutation. Journal of Alzheimer’s Disease. 2000;2(1):47–57. [PubMed]
112. Su JH, Zhao M, Anderson AJ, Srinivasan A, Cotman CW. Activated caspase-3 expression in Alzheimer’s and aged control brain: correlation with Alzheimer pathology. Brain Research. 2001;898(2):350–357. [PubMed]
113. Garcia-Ospina G, Del Rio JM, Lopera F, Velez-Pardo C. Neuronal DNA damage correlates with a positive detection of c-Jun, nuclear factor κB, p53 and Par-4 transcription factors in Alzheimer’s disease. Rev Neurol. 2003;36(11):1004–1010. [PubMed]
114. Thakur A, Wang X, Siedlak SL, Perry G, Smith MA, Zhu X. c-Jun phosphorylation in Alzheimer disease. Journal of Neuroscience Research. 2007;85(8):1668–1673. [PubMed]
115. Ferrer I, Blanco R, Carmona M, et al. Active, phosphorylation-dependent mitogen-activated protein kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in Parkinson’s disease and Dementia with Lewy bodies. Journal of Neural Transmission. 2001;108(12):1383–1396. [PubMed]
116. McLellan ME, Kajdasz ST, Hyman BT, Bacskai BJ. In vivo imaging of reactive oxygen species specifically associated with thioflavine S-positive amyloid plaques by multiphoton microscopy. Journal of Neuroscience. 2003;23(6):2212–2217. [PubMed]
117. Wang C, Li J, Liu Q, et al. Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-κB activation in a rat model of amyloid-beta-induced Alzheimer's disease. Neuroscience Letters. 2011;491(2):127–132. [PubMed]
118. Mogi M, Togari A, Kondo T, et al. Caspase activities and tumor necrosis factor receptor R1 (p55) level are elevated in the substantia nigra from Parkinsonian brain. Journal of Neural Transmission. 2000;107(3):335–341. [PubMed]
119. Mogi M, Kondo T, Mizuno Y, Nagatsu T. p53 protein, interferon-γ, and NF-κB levels are elevated in the parkinsonian brain. Neuroscience Letters. 2007;414(1):94–97. [PubMed]
120. Liang ZQ, Li YL, Zhao XL, et al. NF-κB contributes to 6-hydroxydopamine-induced apoptosis of nigral dopaminergic neurons through p53. Brain Research. 2007;1145(1):190–203. [PubMed]
121. Li LY, Zhao XL, Fei XF, Gu ZL, Qin ZH, Liang ZQ. Bilobalide inhibits 6-OHDA-induced activation of NF-κB and loss of dopaminergic neurons in rat substantia nigra. Acta Pharmacologica Sinica. 2008;29(5):539–547. [PubMed]
122. Muñoz AM, Rey P, Soto-Otero R, Guerra MJ, Labandeira-Garcia JL. Systemic Administration of N-Acetylcysteine Protects Dopaminergic Neurons Against 6-Hydroxydopamine-Induced Degeneration. Journal of Neuroscience Research. 2004;76(4):551–562. [PubMed]
123. Braithwaite SP, Schmid RS, He DN, et al. Inhibition of c-Jun kinase provides neuroprotection in a model of Alzheimer’s disease. Neurobiology of Disease. 2010;39(3):311–317. [PMC free article] [PubMed]
124. Jimenez-Del-Rio M, Daza-Restrepo A, Velez-Pardo C. The cannabinoid CP55,940 prolongs survival and improves locomotor activity in Drosophila melanogaster against paraquat: implications in Parkinson’s disease. Neuroscience Research. 2008;61(4):404–411. [PubMed]
125. Botella JA, Bayersdorfer F, Gmeiner F, Schneuwly S. Modelling Parkinson’s Disease in Drosophila. NeuroMolecular Medicine. 2009;11(4):268–280. [PubMed]
126. Guo M. What have we learned from Drosophila models of Parkinson’s disease? Progress in Brain Research. 2010;184(C):1–16. [PubMed]
127. Chaudhuri A, Bowling K, Funderburk C, et al. Interaction of genetic and environmental factors in a Drosophila parkinsonism model. Journal of Neuroscience. 2007;27(10):2457–2467. [PubMed]
128. Jimenez-Del-Rio M, Guzman-Martinez C, Velez-Pardo C. The effects of polyphenols on survival and locomotor activity in Drosophila melanogaster exposed to iron and paraquat. Neurochemical Research. 2010;35(2):227–238. [PubMed]
129. Ortega-Arellano HF, Jimenez-Del-Rio M, Velez-Pardo C. Life span and locomotor activity modification by glucose and polyphenols in Drosophila melanogaster chronically exposed to oxidative stress-stimuli: implications in Parkinson's disease. Neurochemical Research. 2011;36(6):1073–1086. [PubMed]
130. Zhao B. Natural antioxidants protect neurons in Alzheimer’s disease and parkinson’s disease. Neurochemical Research. 2009;34(4):630–638. [PubMed]
131. Williams RJ, Spencer JPE. Flavonoids, cognition, and dementia: actions, mechanisms, and potential therapeutic utility for Alzheimer disease. Free Radical Biology and Medicine. 2012;52(1):35–45. [PubMed]
132. Bonilla-Ramirez L, Jimenez-Del-Rio M, Velez-Pardo C. Acute and chronic metal exposure impairs locomotion activity in Drosophila melanogaster: a model to study Parkinsonism. BioMetals. 2011;24(6):1045–1057. [PubMed]
133. Clark J, Clore EL, Zheng K, Adame A, Masliah E, Simon DK. Oral N-Acetyl-cysteine attenuates loss of dopaminergic terminals in α-synuclein overexpressing mice. PLoS One. 2010;5(8) Article ID e12333. [PMC free article] [PubMed]
134. Badrick AC, Jones CE. Reorganizing metals: the use of chelating compounds as potential therapies for metal-related neurodegenerative disease. Current Topics in Medicinal Chemistry. 2011;11(5):543–552. [PubMed]
135. Manczak M, Mao P, Calkins MJ, et al. Mitochondria-targeted antioxidants protect against amyloid-β toxicity in Alzheimer’s disease neurons. Journal of Alzheimer’s Disease. 2010;20, supplement 2:S609–S631. [PMC free article] [PubMed]
136. Szeto HH, Schiller PW. Novel therapies targeting inner mitochondrial membrane-from discovery to clinical development. Pharmaceutical Research. 2011;28(11):2669–2679. [PubMed]
137. Orange JS, May MJ. Cell penetrating peptide inhibitors of nuclear factor-kappa B. Cellular and Molecular Life Sciences. 2008;65(22):3564–3591. [PMC free article] [PubMed]
138. Flood PM, Qian L, Peterson LJ, et al. Transcriptional factor NF-κb as a target for therapy in Parkinson's disease. Parkinson's Disease. 2011;2011:8 pages. Article ID 216298. [PMC free article] [PubMed]
139. Zhu X, Yu QS, Cutler RG, et al. Novel p53 inactivators with neuroprotective action: syntheses and pharmacological evaluation of 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole and 2-imino-2,3,4,5,6,7-hexahydrobenzoxazole derivatives. Journal of Medicinal Chemistry. 2002;45(23):5090–5097. [PubMed]
140. Hu C, Li X, Wang W, et al. Design, synthesis, and biological evaluation of imidazoline derivatives as p53-MDM2 binding inhibitors. Bioorganic and Medicinal Chemistry. 2011;19(18):5454–5461. [PubMed]
141. Mehan S, Meena H, Sharma D, Sankhla R. JNK: a stress-activated protein kinase therapeutic strategies and involvement in Alzheimer’s and various neurodegenerative abnormalities. Journal of Molecular Neuroscience. 2010;43(3):376–390. [PubMed]
142. Polytarchou C, Hatziapostolou M, Papadimitriou E. Hydrogen peroxide stimulates proliferation and migration of human prostate cancer cells through activation of activator protein-1 and up-regulation of the heparin affin regulatory peptide gene. Journal of Biological Chemistry. 2005;280(49):40428–40435. [PubMed]
143. Payne SL, Fogelgren B, Hess AR, et al. Lysyl oxidase regulates breast cancer cell migration and adhesion through a hydrogen peroxide-mediated mechanism. Cancer Research. 2005;65(24):11429–11436. [PubMed]
144. Heirman I, Ginneberge D, Brigelius-Flohé R, et al. Blocking tumor cell eicosanoid synthesis by GPx4 impedes tumor growth and malignancy. Free Radical Biology and Medicine. 2006;40(2):285–294. [PubMed]
145. Wang J, Yi J. Cancer cell killing via ROS: to increase or decrease, that is a question. Cancer Biology and Therapy. 2008;7(12):1875–1884. [PubMed]
146. Chen J, Song M, Yu S, et al. Advanced glycation endproducts alter functions and promote apoptosis in endothelial progenitor cells through receptor for advanced glycation endproducts mediate overpression of cell oxidant stress. Molecular and Cellular Biochemistry. 2010;335(1-2):137–146. [PubMed]
147. Małek R, Borowicz KK, Jargiełło M, Czuczwar SJ. Role of nuclear factor kappaB in the central nervous system. Pharmacological Reports. 2007;59(1):25–33. [PubMed]
148. Qin ZH, Tao LY, Chen X. Dual roles of NF-κB in cell survival and implications of NF-κB inhibitors in neuroprotective therapy. Acta Pharmacologica Sinica. 2007;28(12):1859–1872. [PubMed]
149. Bazan NG. Is NF-κB from astrocytes a decision maker of neuronal life or death? (Commentary on Dvoriantchikova et al.): commentary. European Journal of Neuroscience. 2009;30(2):173–174. [PubMed]
150. Bednarski BK, Baldwin AS, Kim HJ. Addressing reported pro-apoptotic functions of NF-κB: targeted inhibition of canonical NF-κB enhances the apoptotic effects of doxorubicin. PLoS One. 2009;4(9) Article ID e6992. [PMC free article] [PubMed]
151. Wang F, Li H, Shi H, Sun B. Pro-apoptotic role of nuclear factor-κB in adriamycin-induced acute myocardial injury in rats. Molecular Medicine Reports. 2012;5(2):400–404. [PubMed]
152. Isaac MGEKN, Quinn R, Tabet N. Vitamin E for Alzheimer’s disease and mild cognitive impairment. Cochrane Database of Systematic Reviews. 2008;(3) Article ID CD002854. [PubMed]
153. Brewer GJ. Why vitamin e therapy fails for treatment of Alzheimer’s disease. Journal of Alzheimer’s Disease. 2010;19(1):27–30. [PMC free article] [PubMed]
154. Snow BJ, Rolfe FL, Lockhart MM, et al. A double-blind, placebo-controlled study to assess the mitochondria- targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease. Movement Disorders. 2010;25(11):1670–1674. [PubMed]
155. Pui CH, Relling MV, Downing JR. Mechanisms of disease: acute lymphoblastic leukemia. New England Journal of Medicine. 2004;350(15):1535–1548. [PubMed]
156. Bonilla-Porras AR, Jimenez-Del-Rio M, Velez-Pardo C. Vitamin K3 and vitamin C alone or in combination induced apoptosis in leukemia cells by a similar oxidative stress signalling mechanism. Cancer Cell International. 2011;11, article 19 [PMC free article] [PubMed]
157. Jomova K, Jenisova Z, Feszterova M, et al. Arsenic: toxicity, oxidative stress and human disease. Journal of Applied Toxicology. 2011;31(2):95–107. [PubMed]
158. Meshkini A, Yazdanparast R. Involvement of oxidative stress in taxol-induced apoptosis in chronic myelogenous leukemia K562 cells. Experimental and Toxicologic Pathology. In press. [PubMed]
159. Bekris LM, Yu CE, Bird TD, Tsuang DW. Review article: genetics of Alzheimer disease. Journal of Geriatric Psychiatry and Neurology. 2010;23(4):213–227. [PMC free article] [PubMed]
160. Bekris LM, Mata IF, Zabetian CP. The genetics of Parkinson disease. Journal of Geriatric Psychiatry and Neurology. 2010;23(4):228–242. [PMC free article] [PubMed]
161. Schapira AH, Gegg M. Mitochondrial contribution to Parkinson’s disease pathogenesis. Parkinson's Disease. 2011;2011:7 pages. Article ID 159160.
162. McCoy MK, Cookson MR. Mitochondrial quality control and dynamics in parkinson's disease. Antioxid Redox Signal. 2012;16(9):869–882. [PMC free article] [PubMed]
163. Vinish M, Anand A, Prabhakar S. Altered oxidative stress levels in Indian Parkinson's disease patients with PARK2 mutations. Acta Biochimica Polonica. 2011;58(2):165–169. [PubMed]
164. Ramsey CP, Giasson BI. The E163K DJ-1 mutant shows specific antioxidant deficiency. Brain Research. 2008;1239(C):1–11. [PMC free article] [PubMed]
165. Ren H, Fu K, Wang D, Mu C, Wang G. Oxidized DJ-1 interacts with the mitochondrial protein BCL-XL. Journal of Biological Chemistry. 2011;286(40):35308–35317. [PMC free article] [PubMed]
166. Heo HY, Park JM, Kim CH, Han BS, Kim KS, Seol W. LRRK2 enhances oxidative stress-induced neurotoxicity via its kinase activity. Experimental cell research. 2010;316(4):649–656. [PubMed]
167. Mohmmad Abdul H, Wenk GL, Gramling M, Hauss-Wegrzyniak B, Butterfield DA. APP and PS-1 mutations induce brain oxidative stress independent of dietary cholesterol: implications for Alzheimer’s disease. Neuroscience Letters. 2004;368(2):148–150. [PubMed]
168. Mohmmad AH, Sultana R, Keller JN, St Clair DK, Markesbery WR, Butterfield DA. Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid beta-peptide (1-42), HO and kainic acid: implications for Alzheimer's disease. Journal of Neurochemistry. 2006;96(5):1322–1335. [PubMed]
169. Ghebranious N, Mukesh B, Giampietro PF, et al. A pilot study of gene/gene and gene/environment interactions in Alzheimer disease. Clinical Medicine and Research. 2011;9(1):17–25. [PubMed]
170. Burbulla LF, Krüger R. Converging environmental and genetic pathways in the pathogenesis of Parkinson's disease. Journal of the Neurological Sciences. 2011;306(1-2):1–8. [PubMed]
171. Gao HM, Hong J-S. Gene-environment interactions: key to unraveling the mystery of Parkinson's disease. Progress in Neurobiology. 2011;94(1):1–19. [PMC free article] [PubMed]
172. Spivey A. Rotenone and paraquat linked to Parkinson's disease: human exposure study supports years of animal studies. Environmental Health Perspectives. 2011;119(6):p. A259. [PMC free article] [PubMed]
173. Sian-Hülsmann J, Mandel S, Youdim MBH, Riederer P. The relevance of iron in the pathogenesis of Parkinson's disease. Journal of Neurochemistry. 2011;118(6):939–957. [PubMed]
174. Qin Y, Zhu W, Zhan C, et al. Investigation on positive correlation of increased brain iron deposition with cognitive impairment in Alzheimer disease by using quantitative MR R2' mapping. Journal of Huazhong University of Science and Technology-Medical Science. 2011;31(4):578–585. [PubMed]
175. Gille G, Reichmann H. Iron-dependent functions of mitochondria—relation to neurodegeneration. Journal of Neural Transmission. 2011;118(3):349–359. [PubMed]
176. Levy OA, Malagelada C, Greene LA. Cell death pathways in Parkinson’s disease: proximal triggers, distal effectors, and final steps. Apoptosis. 2009;14(4):478–500. [PMC free article] [PubMed]
177. Bertrand E, Lechowicz W, Szpak GM, Lewandowska E, Dymecki J, Wierzba-Bobrowicz T. Limbic neuropathology in idiopathic Parkinson’s disease with concomitant dementia. Folia Neuropathologica. 2004;42(3):141–150. [PubMed]
178. Ramirez A, Heimbach A, Gründemann J, et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nature Genetics. 2006;38(10):1184–1191. [PubMed]
179. Compta Y, Parkkinen L, O'Sullivan SS, et al. Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important? Brain. 2011;134(5):1493–1505. [PMC free article] [PubMed]
180. Oda A, Tamaoka A, Araki W. Oxidative stress up-regulates presenilin 1 in lipid rafts in neuronal cells. Journal of Neuroscience Research. 2010;88(5):1137–1145. [PubMed]
181. Jo D-G, Arumugam TV, Woo H-N, et al. Evidence that γ-secretase mediates oxidative stress-induced β-secretase expression in Alzheimer's disease. Neurobiology of Aging. 2010;31(6):917–925. [PMC free article] [PubMed]
182. Iijima-Ando K, Iijima K. Transgenic Drosophila models of Alzheimer's disease and tauopathies. Brain Structure and Function. 2010;214(2-3):245–262. [PMC free article] [PubMed]
183. Bonner JM, Boulianne GL. Drosophila as a model to study age-related neurodegenerative disorders: Alzheimer's disease. Experimental Gerontology. 2011;46(5):335–339. [PubMed]
184. Park J, Kim Y, Chung J. Mitochondrial dysfunction and Parkinson’s disease genes: insights from Drosophila. DMM Disease Models and Mechanisms. 2009;2(7-8):336–340. [PubMed]
185. Whitworth AJ. Drosophila models of Parkinson's disease. Advances in Genetics. 2011;73:1–50. [PubMed]
186. Sang TK, Chang HY, Lawless GM, et al. A Drosophila model of mutant human parkin-induced toxicity demonstrates selective loss of dopaminergic neurons and dependence on cellular dopamine. Journal of Neuroscience. 2007;27(5):981–992. [PubMed]
187. Wang C, Lu R, Ouyang X, et al. Drosophila overexpressing parkin R275W mutant exhibits dopaminergic neuron degeneration and mitochondrial abnormalities. Journal of Neuroscience. 2007;27(32):8563–8570. [PubMed]
188. Clark IE, Dodson MW, Jiang C, et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature. 2006;441(7097):1162–1166. [PubMed]
189. Feany MB, Bender WW. A Drosophila model of Parkinson’s disease. Nature. 2000;404(6776):394–398. [PubMed]
190. Liu Z, Wang X, Yu Y, et al. A Drosophila model for LRRK2-linked parkinsonism. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(7):2693–2698. [PubMed]
191. Lavara-Culebras E, Paricio N. Drosophila DJ-1 mutants are sensitive to oxidative stress and show reduced lifespan and motor deficits. Gene. 2007;400(1-2):158–165. [PubMed]
192. Moore DJ, Zhang L, Troncoso J, et al. Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Human Molecular Genetics. 2005;14(1):71–84. [PubMed]
193. Jendrach M, Gispert S, Ricciardi F, Klinkenberg M, Schemm R, Auburger G. The mitochondrial kinase PINK1, stress response and Parkinson's disease. Journal of Bioenergetics and Biomembranes. 2009;41(6):481–486. [PubMed]
194. Angeles DC, Gan B-H, Onstead L, et al. Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death. Human Mutation. 2011;32(12):1390–1397. [PubMed]
195. Wang H-L, Chou A-H, Wu A-S, et al. PARK6 PINK1 mutants are defective in maintaining mitochondrial membrane potential and inhibiting ROS formation of substantia nigra dopaminergic neurons. Biochimica et Biophysica Acta. 2011;1812(6):674–684. [PubMed]
196. Park J, Lee SB, Lee S, et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature. 2006;441(7097):1157–1161. [PubMed]
197. Hao LY, Giasson BI, Bonini NM. DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(21):9747–9752. [PubMed]
198. Korey CA. We hold these truths to be self-evident, that all flies and men are created equal: recent progress on human disease models. Fly. 2007;1(2):118–122. [PubMed]
199. Bertoni JM, Arlette JP, Fernandez HH, et al. North American Parkinson's and melanoma survey investigators. increased melanoma risk in Parkinson disease: a prospective clinicopathological study. Archives of Neurology. 2010;67(3):347–352. [PubMed]
200. Liu R, Gao X, Lu Y, Chen H. Meta-analysis of the relationship between Parkinson disease and melanoma. Neurology. 2011;76(23):2002–2009. [PMC free article] [PubMed]
201. Pan T, Li X, Jankovic J. The association between Parkinson's disease and melanoma. International Journal of Cancer. 2011;128(10):2251–2260. [PubMed]
202. Veeriah S, Taylor BS, Meng S, et al. Somatic mutations of the Parkinson’s disease-associated gene PARK2 in glioblastoma and other human malignancies. Nature Genetics. 2010;42(1):77–82. [PMC free article] [PubMed]
203. Zhang C, Lin M, Wu R, et al. Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(39):16259–16264. [PubMed]
204. da Costa CA, Sunyach C, Giaime E, et al. Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson’s disease. Nature Cell Biology. 2009;11(11):1370–1375. [PMC free article] [PubMed]
205. Alves da Costa C, Checler F. Apoptosis in Parkinson’s disease: is p53 the missing link between genetic and sporadic Parkinsonism? Cellular Signalling. 2010;23(6):963–968. [PubMed]
206. Schneider G, Kramer OH. NFκB/p53 crosstalk-a promising new therapeutic target. Biochimica et Biophysica Acta. 2011;1815(1):90–103. [PubMed]
207. Pandey KB, Rizvi SI. Plant polyphenols as dietary antioxidants in human health and disease. Oxidative Medicine and Cellular Longevity. 2009;2(5):270–278. [PMC free article] [PubMed]
208. Darvesh AS, Carroll RT, Bishayee A, Geldenhuys WJ, Van Der Schyf CJ. Oxidative stress and Alzheimer’s disease: dietary polyphenols as potential therapeutic agents. Expert Review of Neurotherapeutics. 2010;10(5):729–745. [PubMed]
209. Ghosh N, Ghosh R, Mandal SC. Antioxidant protection: a promising therapeutic intervention in neurodegenerative disease. Free Radical Research. 2011;45(8):888–905. [PubMed]
210. Halliwell B. Dietary polyphenols: good, bad, or indifferent for your health? Cardiovascular Research. 2007;73(2):341–347. [PubMed]
211. Halliwell B. Are polyphenols antioxidants or pro-oxidants? What do we learn from cell culture and in vivo studies? Archives of Biochemistry and Biophysics. 2008;476(2):107–112. [PubMed]
212. Schaffer S, Halliwell B. Do polyphenols enter the brain and does it matter? Some theoretical and practical considerations. Genes & Nutrition. 2012;7(2):99–109. [PMC free article] [PubMed]
213. Visioli F, de la Lastra CA, Andres-Lacueva C, et al. Polyphenols and human health: a prospectus. Critical Reviews in Food Science and Nutrition. 2011;51(6):524–546. [PubMed]
214. Kieburtz K, Ravina B. Why hasn't neuroprotection worked in Parkinson's disease? Nature Clinical Practice Neurology. 2007;3(5):240–241. [PubMed]

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