Oxidative stress and Alzheimer disease: the autophagy connection?

Intraneuronal accumulation of amyloid beta-protein (Abeta) is believed to be responsible for degeneration and apoptosis of neurons and consequent senile plaque formation in Alzheimer disease (AD), the main cause of senile dementia. Oxidative stress, an early determinant of AD, has been recently found to induce intralysosomal Abeta accumulation in cultured differentiated neuroblastoma cells through activation of macroautophagy. Because Abeta is known to destabilize lysosomal membranes, potentially resulting in apoptotic cell death, this finding suggests the involvement of oxidative stress-induced macroautophagy in the pathogenesis of AD.     

Oxidative stress and cancer: have we moved forward?

'Reactive species' (RS) of various types are formed in vivo and many are powerful oxidizing agents, capable of damaging DNA and other biomolecules. Increased formation of RS can promote the development of malignancy, and the 'normal' rates of RS generation may account for the increased risk of cancer development in the aged. Indeed, knockout of various antioxidant defence enzymes raises oxidative damage levels and promotes age-related cancer development in animals. In explaining this, most attention has been paid to direct oxidative damage to DNA by certain RS, such as hydroxyl radical (OH*). However, increased levels of DNA base oxidation products such as 8OHdg (8-hydroxy-2'-deoxyguanosine) do not always lead to malignancy, although malignant tumours often show increased levels of DNA base oxidation. Hence additional actions of RS must be important, possibly their effects on p53, cell proliferation, invasiveness and metastasis. Chronic inflammation predisposes to malignancy, but the role of RS in this is likely to be complex because RS can sometimes act as anti-inflammatory agents.     

Oxidative stress and neurodegeneration: where are we now?

The brain and nervous system are prone to oxidative stress, and are inadequately equipped with antioxidant defense systems to prevent 'ongoing' oxidative damage, let alone the extra oxidative damage imposed by the neurodegenerative diseases. Indeed, increased oxidative damage, mitochondrial dysfunction, accumulation of oxidized aggregated proteins, inflammation, and defects in protein clearance constitute complex intertwined pathologies that conspire to kill neurons. After a long lag period, therapeutic and other interventions based on a knowledge of redox biology are on the horizon for at least some of the neurodegenerative diseases.     

Oxidative stress and antioxidants: a link to disease and prevention?

The thrust of this presentation takes a more programmatic approach and gives an overview of the programs at the NIH and the NCI that have a broad nutritional and basic science undercurrent and outline. Also discussed briefly are some areas of general concern that are under investigation in the nutrition group and are included in the group's outreach efforts among professional and academic organizations. The overarching focus of these efforts is to stress the importance of nutrition as a potential modulator of health/disease risks associated with genetic predisposition and environmentally induced disease from diet, lifestyle and exposure to pollutants.     

Oxidative stress and ageing: is ageing a cysteine deficiency syndrome?

Reactive oxygen species (ROS) are constantly produced in biological tissues and play a role in various signalling pathways. Abnormally high ROS concentrations cause oxidative stress associated with tissue damage and dysregulation of physiological signals. There is growing evidence that oxidative stress increases with age. It has also been shown that the life span of worms, flies and mice can be significantly increased by mutations which impede the insulin receptor signalling cascade. Molecular studies revealed that the insulin-independent basal activity of the insulin receptor is increased by ROS and downregulated by certain antioxidants. Complementary clinical studies confirmed that supplementation of the glutathione precursor cysteine decreases insulin responsiveness in the fasted state. In several clinical trials, cysteine supplementation improved skeletal muscle functions, decreased the body fat/lean body mass ratio, decreased plasma levels of the inflammatory cytokine tumour necrosis factor alpha (TNF-alpha), improved immune functions, and increased plasma albumin levels. As all these parameters degenerate with age, these findings suggest: (i) that loss of youth, health and quality of life may be partly explained by a deficit in cysteine and (ii) that the dietary consumption of cysteine is generally suboptimal and everybody is likely to have a cysteine deficiency sooner or later.     

Yeast chronological lifespan and proteotoxic stress: is autophagy good or bad?

Autophagy, a highly conserved proteolytic mechanism of quality control, is essential for the maintenance of metabolic and cellular homoeostasis and for an efficient cellular response to stress. Autophagy declines with aging and is believed to contribute to different aspects of the aging phenotype. The nutrient-sensing pathways PKA (protein kinase A), Sch9 and TOR (target of rapamycin), involved in the regulation of yeast lifespan, also converge on a common targeted process: autophagy. The molecular mechanisms underlying the regulation of autophagy and aging by these signalling pathways in yeast, with special attention to the TOR pathway, are discussed in the present paper. The question of whether or not autophagy could contribute to yeast cell death occurring during CLS (chronological lifespan) is discussed in the light of our findings obtained after autophagy activation promoted by proteotoxic stress. Autophagy progressively increases in cells expressing the aggregation-prone protein α-synuclein and seems to participate in the early cell death and shortening of CLS under these conditions, highlighting that autophagic activity should be maintained below physiological levels to exert its promising anti-aging effects.     

Oxidative stress and antioxidative defense in cephalopods: a function of metabolic rate or age?

Activities of the antioxidative enzymes superoxide dismutase (SOD), catalase, glutathione peroxidase (GPX) and glutathione reductase (GR) were measured in the cephalopods Sepia officinalis and Lolliguncula brevis. Maximal enzyme activities were higher in gill tissue than in the mantle musculature of both species. Activities were generally lower in tissues of L. brevis than in S. officinalis. Comparison with other ectothermic animals showed both cephalopod species to have a low enzymatic antioxidative status despite their high metabolic rate. Furthermore, changes in antioxidative enzyme activities were measured in the cuttlefish S. officinalis with increasing age. The concentrations of malondialdehyde (MDA) and lipofuscin were determined as indicators of lipid peroxidation. Investigated animals were between 1.5 months and over 12 months old. Changes of antioxidative enzyme activities with age were not uniform. SOD and GPX activities increased with age, while catalase activity declined. In contrast, GR activity remained almost unchanged in all age groups. The low level of antioxidative defense might allow for the significant age-induced rise in MDA levels in gills and mantle musculature and for the increase in lipofuscin levels in mantle and brain tissue. It might thereby contribute to increased oxidative damage and a short life span in these cephalopods.     

Oxidative stress and vascular disease in diabetes: is the dichotomization of insulin signaling still valid?

The current wisdom indicates that insulin's positive effects, normoglycemia, vasodilation, and anti-inflammation, are mediated by the canonical phosphoinositide 3-kinase (PI3K)/Akt pathway whereas the negative effects are mediated by the mitogen-activated protein kinase (MAPK)/extracellular regulated kinase (ERK) pathway. Much of the intracellular oxidant stress is mediated by the MAPK/ERK pathway which is a downstream signal also for other proatherogenic hormones such as angiotensin II. However, recent evidence links MAPK activation to antioxidant activity and vascular protection. We argue against a dichotomization of insulin signaling also in light of the concept that ERK-MAPK represents a critical node in the intracellular insulin network responsible for several positive effects related not only to vascular function but also to life span.     

Oxidative stress in acute pancreatitis: lost in translation?

Abstract

Oxidative stress has been implicated in the pathogenesis of acute pancreatitis, a severe and debilitating inflammation of the pancreas that carries a significant mortality, and which imposes a considerable financial burden on the health system due to patient care. Although extensive efforts have been directed towards the elucidation of critical underlying mechanisms and the identification of novel therapeutic targets, the disease remains without a specific therapy. In experimental animal models of acute pancreatitis, increased oxidative stress and decreased antioxidant defences have been observed, changes also detected in patients clinically. However, despite the promise of studies evaluating the effects of antioxidants in these model systems, translation to the clinic has thus far been disappointing. This may reflect many factors involved in the design of both preclinical and clinical evaluations of antioxidant therapy, not least the fact that most experimental studies have focussed on pre-treatment rather than post-injury assessment. This review has examined evidence relating to the involvement of oxidative stress in the pathophysiology of acute pancreatitis, focussing on experimental models and the clinical experience, including the experimental techniques employed and potential of antioxidant therapy.     

Oxidative stress in cell culture: an under-appreciated problem?

Cell culture studies have given much valuable information about mechanisms of metabolism and signal transduction and of regulation of gene expression, proliferation, senescence, and death. However, cells in culture may behave differently from cells in vivo in many ways. One of these is that cell culture imposes a state of oxidative stress on cells. I argue that cells that survive and grow in culture might use ROS-dependent signal transduction pathways that rarely or never operate in vivo. A further problem is that cell culture media can catalyse the oxidation of compounds added to them, resulting in apparent cellular effects that are in fact due to oxidation products such as ROS. Such artefacts may have affected many studies on the effects of ascorbate, thiols, flavonoids and other polyphenolic compounds on cells in culture.     

Oxidative stress in cardiovascular disease: myth or fact?

Oxidative stress is a mechanism with a central role in the pathogenesis of atherosclerosis, cancer, and other chronic diseases. It also plays a major role in the aging process. Ischemic heart disease is perhaps the human condition in which the role of oxidative stress has been investigated in more detail: reactive oxygen species and consequent expression of oxidative damage have been demonstrated during post-ischemic reperfusion in humans and the protective role of antioxidants has been validated in several experimental studies addressing the pathophysiology of acute ischemia. Although an impressive bulk of experimental studies substantiate the role of oxidative stress in the progression of the damage induced by acute ischemia, not a single pathophysiologic achievement has had a significant impact on the treatment of patients and randomized, controlled clinical trials, both in primary and secondary prevention, have failed to prove the efficacy of antioxidants in the treatment of ischemic cardiovascular disease. This dichotomy, between the experimental data and the lack of impact in the clinical setting, needs to be deeply investigated: certainly, the pathophysiologic grounds of oxidative stress do maintain their validity but the concepts of the determinants of oxidative damage should be critically revised. In this regard, the role of intermediate metabolism during myocardial ischemia together with the cellular redox state might represent a promising interpretative key.     

Oxidative stress induces macroautophagy of amyloid β-protein and ensuing apoptosis

There is increasing evidence for the toxicity of intracellular amyloid β-protein (Aβ) to neurons and the involvement of lysosomes in this process in Alzheimer disease (AD). We have recently shown that oxidative stress, a recognized determinant of AD, enhances macroautophagy and leads to intralysosomal accumulation of Aβ in cultured neuroblastoma cells. We hypothesized that oxidative stress promotes AD by stimulating macroautophagy of Aβ that further may induce cell death by destabilizing lysosomal membranes. To investigate such possibility, we compared the effects of hyperoxia (40% ambient oxygen) in cultured HEK293 cells that were transfected with an empty vector (Vector), wild-type APP (APPwt), or Swedish mutant APP (APPswe). Exposure to hyperoxia for 5 days increased the number of cells with Aβ-containing lysosomes, as well as the number of apoptotic cells, compared to normoxic conditions. The rate of apoptosis in all three cell lines demonstrated dependence on intralysosomal Aβ content (Vector < APPwt < APPswe). Furthermore, the degree of apoptosis was positively correlated with lysosomal membrane permeabilization, whereas inhibitors of macroautophagy and lysosomal function decreased oxidant-induced apoptosis and diminished the differences in apoptotic response between different cell lines. These results suggest that oxidative stress can induce neuronal death through macroautophagy of Aβ and consequent lysosomal membrane permeabilization, which may help explain the mechanisms behind neuronal loss in AD.     

Oxidative stress: a theoretical model or a biological reality?

Although oxidative stress has been extensively studied the last fifteen years, many physicians and biologists are still sceptical concerning its interest in biology and medicine. This is probably due, in part, to the fact that this subject is a matter of biophysics, and the first studies reported were written using a physical language that inspired these people used to a more concrete problematic very little. Another problem is the difficulty to detect the species mediating oxidative stress, and to determine their role in biological processes. This review is aimed at presenting oxidative stress, as well as reactive oxygen species and free radicals--the molecules that mediate it--in a clear form able to convince all researchers involved in life sciences that these short-lived intermediates are indissociable from any aerobic organism. Moreover, if reactive oxygen species and free radicals are undoubtedly involved in many pathologies, they have physiological functions too.     

Non-canonical autophagy: an exception or an underestimated form of autophagy?

Macroautophagy (hereafter called autophagy) is a dynamic and evolutionarily conserved process used to sequester and degrade cytoplasm and entire organelles in a sequestering vesicle with a double membrane, known as the autophagosome, which ultimately fuses with a lysosome to degrade its autophagic cargo. Recently, we have unraveled two distinct forms of autophagy in cancer cells, which we term canonical and non-canonical autophagy. In contrast to classical or canonical autophagy, non-canonical autophagy is a process that does not require the entire set of autophagy-related (Atg) proteins in particular Beclin 1, to form the autophagosome. Non-canonical autophagy is therefore not blocked by the knockdown of Beclin 1 or of its binding partner hVps34. Moreover overexpression of Bcl-2, which is known to block canonical starvation-induced autophagy by binding to Beclin 1, is unable to reverse the non-canonical autophagy triggered by the polyphenol resveratrol in the breast cancer MCF-7 cell line. In MCF-7 cells, at least, non-canonical autophagy is involved in the caspase-independent cell death induced by resveratrol.     

Oxidative/nitrative stress in the pathogenesis of systemic sclerosis: are antioxidants beneficial?

Abstract

Systemic sclerosis (SSc) is a multisystem autoimmune disease: characterised from the clinical side by progressive vasculopathy and fibrosis of the skin and different organs and from the biochemical side by fibroblast deregulation with excessive production of collagen and increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). The latter contributes to an overproduction of reactive oxygen species that through an autocrine loop maintains NOX4 in a state of activation. Reactive oxygen and nitrogen species are implicated in the origin and perpetuation of several clinical manifestations of SSc having vascular damage in common; attempts to dampen oxidative and nitrative stress through different agents with antioxidant properties have not translated into a sustained clinical benefit. Objective of this narrative review is to describe the origin and clinical implications of oxidative and nitrative stress in SSc, with particular focus on the central role of NOX4 and its interactions, to re-evaluate the antioxidant approaches so far used to limit disease progression, to appraise the complexity of antioxidant treatment and to touch on novel pathways elements of which may represent specific treatment targets in the not so distant future.     

Non-canonical autophagy: An exception or an underestimated form of autophagy?

Macroautophagy (hereafter called autophagy) is a dynamic and evolutionarily conserved process used to sequester and degrade cytoplasm and entire organelles in a sequestering vesicle with a double membrane, known as the autophagosome, which ultimately fuses with a lysosome to degrade its autophagic cargo. Recently, we have unraveled two distinct forms of autophagy in cancer cells, which we term canonical and non-canonical autophagy. In contrast to classical or canonical autophagy, non-canonical autophagy is a process that does not require the entire set of autophagy-related (Atg) proteins in particular Beclin 1, to form the autophagosome. Non-canonical autophagy is therefore not blocked by the knockdown of Beclin 1 or of its binding partner hVps34. Moreover overexpression of Bcl-2, which is known to block canonical starvation-induced autophagy by binding to Beclin 1, is unable to reverse the non-canonical autophagy triggered by the polyphenol resveratrol in the breast cancer MCF-7 cell line. In MCF-7 cells, at least, non-canonical autophagy is involved in the caspase-independent cell death induced by resveratrol.     

p53: The Janus of autophagy?

The autophagy pathway functions in adaptation to nutrient stress and tumour suppression. The p53 tumour suppressor, previously thought to positively regulate autophagy, may also inhibit it. This dual interplay between p53 and autophagy regulation is enigmatic, but may underlie key aspects of metabolism and cancer biology.