The role of oxidative stress in anxiety disorder: cause or consequence?

Anxiety disorders are the most common mental illness in the USA affecting 18% of the population. The cause(s) of anxiety disorders is/are not completely clear, and research in the neurobiology of anxiety at the molecular level is still rather limited. Although mounting clinical and preclinical evidence now indicates that oxidative stress may be a major component of anxiety pathology, whether oxidative stress is the cause or consequence remains elusive. Studies conducted over the past few years suggest that anxiety disorders may be characterised by lowered antioxidant defences and increased oxidative damage to proteins, lipids, and nucleic acids. In particular, oxidative modifications to proteins have actually been proposed as a potential factor in the onset and progression of several psychiatric disorders, including anxiety and depressive disorders. Oxidised proteins are normally degraded by the proteasome proteolytic complex in the cell cytoplasm, nucleus, and endoplasmic reticulum. The Lon protease performs a similar protective function inside mitochondria. Impairment of the proteasome and/or the Lon protease results in the accumulation of toxic oxidised proteins in the brain, which can cause severe neuronal trauma. Recent evidence points to possible proteolytic dysfunction and accumulation of damaged, oxidised proteins as factors that may determine the appearance and severity of psychotic symptoms in mood disorders. Thus, critical interactions between oxidative stress, proteasome, and the Lon protease may provide keys to the molecular mechanisms involved in emotional regulation, and may also be of great help in designing and screening novel anxiolytics and antidepressants.     

Update on the oxidative stress theory of aging: Does oxidative stress play a role in aging or healthy aging?

The oxidative stress theory of aging predicts that manipulations that alter oxidative stress/damage will alter aging. The gold standard for determining whether aging is altered is life span, i.e., does altering oxidative stress/damage change life span? Mice with genetic manipulations in their antioxidant defense system designed to directly address this prediction have, with few exceptions, shown no change in life span. However, when these transgenic/knockout mice are tested using models that develop various types of age-related pathology, they show alterations in progression and/or severity of pathology as predicted by the oxidative stress theory: increased oxidative stress accelerates pathology and reduced oxidative stress retards pathology. These contradictory observations might mean that (a) oxidative stress plays a very limited, if any, role in aging but a major role in health span and/or (b) the role that oxidative stress plays in aging depends on environment. In environments with minimal stress, as expected under optimal husbandry, oxidative damage plays little role in aging. However, under chronic stress, including pathological phenotypes that diminish optimal health, oxidative stress/damage plays a major role in aging. Under these conditions, enhanced antioxidant defenses exert an “antiaging” action, leading to changes in life span, age-related pathology, and physiological function as predicted by the oxidative stress theory of aging.     

Which comes first: Renal inflammation or oxidative stress in spontaneously hypertensive rats?

The present study was undertaken to identify whether inflammation or oxidative stress is the primary abnormality in the kidney in spontaneously hypertensive rats (SHR). Renal inflammation and oxidative stress were evaluated in 2- and 3-week-old prehypertensive SHR and age-matched genetically normotensive control Wistar-Kyoto (WKY) rats. Blood pressure was similar in WKY and SHR rats at 2 and 3 weeks, of age. Renal inflammation (macrophage and nuclear factor-κB) was elevated in SHR at 3 weeks, but not at 2 weeks, of age compared with age-matched WKY rats. Renal oxidative stress (nitrotyrosine, 8-hydroxy-2′-deoxyguanosine and p47phox) was also clearly elevated in 3-week-old SHR compared with age-matched WKY rats. Additionally, NADPH oxidase subunit p47phox was found elevated in 2-week-old SHR compared to age-matched WKY rats. Moreover, antioxidant (N-acetyl-l-cysteine and Tempol) treatment reduced renal inflammation in prehypertensive SHR. We therefore conclude that the oxidative stress appears before inflammation as a primary abnormality in the kidney in prehypertensive SHR.     

Which comes first: renal inflammation or oxidative stress in spontaneously hypertensive rats?

The present study was undertaken to identify whether inflammation or oxidative stress is the primary abnormality in the kidney in spontaneously hypertensive rats (SHR). Renal inflammation and oxidative stress were evaluated in 2- and 3-week-old prehypertensive SHR and age-matched genetically normotensive control Wistar-Kyoto (WKY) rats. Blood pressure was similar in WKY and SHR rats at 2 and 3 weeks, of age. Renal inflammation (macrophage and nuclear factor-kappaB) was elevated in SHR at 3 weeks, but not at 2 weeks, of age compared with age-matched WKY rats. Renal oxidative stress (nitrotyrosine, 8-hydroxy-2'-deoxyguanosine and p47phox) was also clearly elevated in 3-week-old SHR compared with age-matched WKY rats. Additionally, NADPH oxidase subunit p47phox was found elevated in 2-week-old SHR compared to age-matched WKY rats. Moreover, antioxidant (N-acetyl-L-cysteine and Tempol) treatment reduced renal inflammation in prehypertensive SHR. We therefore conclude that the oxidative stress appears before inflammation as a primary abnormality in the kidney in prehypertensive SHR.     

Arabinogalactan proteins: actors or spectators during abiotic and biotic stress in plants?

Arabinogalactan proteins (AGPs) are a family of hydroxyproline-rich glycoproteins (HRGP) ubiquitous in the plant kingdom. They are probably one of the most heterogeneous and complex families of macromolecules, making them able to perform different and multiple functions. Located at the plasma membrane–cell wall interface, AGPs are involved in several processes, from plant growth and development to reproduction. An additional function of AGPs in response to biotic and abiotic stress has been suggested by several studies. The purpose of this review is to summarize critically and analytically the available knowledge on the effects of abiotic stress (low and high temperatures, drought, flooding, anoxia and metal deficiency/toxicity) and biotic stress (bacteria, fungi, nematodes and viruses) on AGPs. A deeper understanding of the role of AGPs during these conditions can be an important tool for understanding AGP biology and for the possible development of efficient breeding strategies.     

Aging: is oxidative stress a marker or is it causal?

Rapid developments in free radical biology and molecular technology have permitted exploration of the free radical theory of aging. Oxidative stress has also been implicated in the pathogenesis of a number of diseases. Studies have found evidence of oxidative damage to macromolecules (DNA, lipids, protein), and data in transgenic Drosophila melanogaster support the hypothesis that oxidative injury might directly cause the aging process. Additional links between oxidative stress and aging focus on mitochondria, leading to development of the mitochondrial theory of aging. However, despite the number of studies describing the association of markers of oxidative damage with advancing age, few, if any definitively link oxidative injury to altered energy production or cellular function. Although a causal role for oxidative stress in the aging process has not been clearly established, this does not preclude attempts to reduce oxidative injury as a means to reduce morbidity and perhaps increase the healthy, useful life span of an individual. This review highlights studies demonstrating enhanced oxidative stress with advancing age and stresses the importance of the balance between oxidants as mediators of disease and important components of signal transduction pathways.     

Effect of arsenic–phosphorus interaction on arsenic-induced oxidative stress in chickpea plants

Arsenic-induced oxidative stress in chickpea was investigated under glasshouse conditions in response to application of arsenic and phosphorus. Three levels of arsenic (0, 30 and 60 mg kg^?1) and four levels of P (50, 100, 200, and 400 mg kg^?1) were applied to soil-grown plants. Increasing levels of both arsenic and P significantly increased arsenic concentrations in the plants. Shoot growth was reduced with increased arsenic supply regardless of applied P levels. Applied arsenic induced oxidative stress in the plants, and the concentrations of H₂O₂ and lipid peroxidation were increased. Activity of superoxide dismutase (SOD) and concentrations of non-enzymatic antioxidants decreased in these plants, but activities of catalase (CAT) and ascorbate peroxidase (APX) were significantly increased under arsenic phytotoxicity. Increased supply of P decreased activities of CAT and APX, and decreased concentrations of non-enzymatic antioxidants, but the high-P plants had lowered lipid peroxidation. It can be concluded that P increased uptake of arsenic from the soil, probably by making it more available, but although plant growth was inhibited by arsenic the P may have partially protected the membranes from arsenic-induced oxidative stress.     

Lymphocyte 5'-ectonucleotidase: an indicator of oxidative stress in humans?

Lymphocytic 5'-ectonucleotidase (NT) activity previously has been shown to be reduced in patients with a high pro-oxidant state. This study shows that NT activity is decreased in vitro by exposure to superoxide anions and that ascorbate protects against this effect. Also, a putative high pro-oxidant state in vivo, as indicated by low tissue ascorbate levels, resulted in a significant decrease in NT which an antioxidant intake normalized. These results taken together suggest that NT is sensitive to superoxide anion and that it may be a good marker of a pro-oxidant state in humans.     

A change of heart: oxidative stress in governing muscle function?

Biophysical Reviews - Redox/cysteine modification of proteins that regulate calcium cycling can affect contraction in striated muscles. Understanding the nature of these modifications would present...     

Facilitation of tree saplings by nurse plants: Microhabitat amelioration or protection against herbivores?

Question: Positive interactions are predicted to be common in communities developing under high physical stress or high herbivory pressure due to neighbour amelioration of limiting physical and consumer stresses, respectively. However, when both stress sources meet in the same community, the relative importance of the two facilitation mechanisms is poorly understood. We ask: What is the relative importance of abiotic vs. biotic mechanisms of facilitation of tree saplings by shrubs in Mediterranean mountain forests? Location: Sierra Nevada, SE Spain (1800–1850 m a.s.l.) Methods: Saplings of four tree taxa (Acer opalus ssp. grana‐tense, Quercus ilex, Pinus nigra ssp. salzmanii and P. sylvestris var. nevadensis) were planted following a 2 × 2 factorial design: two levels of herbivory (control and ungulate exclusion) and two microhabitats (under shrubs and in open areas). Sapling survival and growth were monitored for five years. Results: Shrubs had positive effects on sapling survival both in control and ungulate excluded plots. This effect was species‐specific, with shrubs increasing the survival of Acer opalus and Quercus ilex three and twofold, respectively, but having a minor effect on the Pinus species. Herbivory damage was also species‐specific, being much higher for Acer opalus than for any other species. Shrubs did not protect saplings of any species against ungulates. Thus, all Acer saplings (the most damaged species) suffered herbivory outside the exclosures, which largely reduced sapling height. Conclusions: Protection from abiotic stress (summer drought and winter frost) was much more relevant than protection from biotic stress (herbivory). However, we propose that the final balance between the two mechanisms can be expected to vary strongly between sites, depending on the relative magnitude of the different sources of stress and the intrinsic traits (e.g. palatability) of the species interacting.     

Toxin-antitoxin pairs in bacteria: killers or stress regulators?

Plasmid toxin-antitoxin systems, which kill daughter cells that fail to inherit the plasmid genome, have chromosomal homologs in eubacteria and archaea. In this issue of Cell, Pederson et al. show that the E. coli RelE toxin cleaves mRNA in the ribosomal A site, potentially allowing it to function as a stress regulator during amino acid starvation.     

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.     

MAPK signalling in cellular metabolism: stress or wellness?

Mitogen-activated protein kinase (MAPK) signalling occurs in response to almost any change in the extracellular or intracellular milieu that affects the metabolism of the cell, organ or the entire organism. MAPK-dependent signal transduction is required for physiological metabolic adaptation, but inappropriate MAPK signalling contributes to the development of several interdependent pathological traits, collectively known as metabolic syndrome. Metabolic syndrome leads to life-threatening clinical consequences, such as type 2 diabetes. This Review provides an overview of the MAPK-signalling mechanisms that underly basic cellular metabolism, discussing their link to disease.     

Fuegian plants in Antarctica: natural or anthropogenically assisted immigrants?

Two species of flowering plant of Fuegian montane provenance have been discovered on Deception Island in the maritime Antarctic, 950 km south of South America. Four individuals of Nassauvia magellanica and one of Gamochaeta nivalis (both Asteraceae) are growing robustly and in close proximity of each other on dry ash and scoria soil near a ruined whaling station which, in recent years, has been frequently visited by large numbers of ship-borne tourists. The Protocol on Environmental Protection to the Antarctic Treaty and the Management Plan for the island, designated an Antarctic Specially Managed Area, provide strict regulations for the conduct of visitors to this site and precautions against the accidental introduction of non-indigenous species. While their establishment on this remote volcanic island may have been anthropogenically mediated, natural immigration cannot be ruled out as both species produce seed adapted for wind-dispersal in their native Tierra del Fuego. The ecological consequences if one or both of these aliens spreads beyond their present restricted location are considered. While determined efforts are being made to implement rigorous biosecurity measures in Antarctica, current Antarctic Treaty policy on dealing with colonizing invasive alien species is indecisive and requires urgent action and clear recommendations.     

Damage site chromatin: open or closed?

Technical advances in recent years, such as laser microirradiation and chromatin immunoprecipitation, have led to further understanding of DNA damage responses and repair processes as they happen in vivo and have allowed us to better evaluate the activities of new factors at damage sites. Facilitated by these tools, recent studies identified the unexpected roles of heterochromatin factors in DNA damage recognition and repair, which also involves poly(ADP-ribose) polymerases (PARPs). The results suggest that chromatin at damage sites may be quite structurally dynamic during the repair process, with transient intervals of 'closed' configurations before a more 'open' arrangement that allows the repair machinery to access damaged DNA.     

Multiple or multiphasic uptake mechanisms in plants?

Abstract Borstlap (1983) has alleged that (a) there are no abrupt changes in curves for the concentration dependence of solute uptake in plants, and (b) many such uptake isotherms may be described by the sum of two Michaelis-Menten terms and a linear term. These claims are considered in detail in connection with the recent finding (Nandi, Pant & Nissen, 1987) that phosphate uptake by corn roots increased more rapidly within the higher phases, i.e. at high external phosphate concentrations, but also levelled off faster than predicted from Michaelis-Menten kinetics. Similar deviations are, in retrospect, also found for uptake of other solutes and result in fewer phases at high external solute concentrations. The simplified and strikingly similar multiphasic patterns in the present paper show that (a) the abrupt changes in published isotherms are not due to error in the data, and (b) uptake isotherms cannot be adequately represented by the sum of two Michaelis-Menten terms and a linear term, or by similar continuous functions, if sufficiently detailed and precise data are used. These findings are not consistent with the existence of multiple uptake mechanisms, including free diffusion, in the plasmalemma. Uptake occurs instead by a single, multiphasic mechanism for each solute or group of related solutes. The similarities in the multiphasic patterns indicate, furthermore, that influx of the various solutes may be coupled.     

Lymphocyte 5′-ectonucleotidase: an indicator of oxidative stress in humans?

Abstract

Lymphocytic 5′-ectonucleotidase (NT) activity previously has been shown to be reduced in patients with a high pro-oxidant state. This study shows that NT activity is decreased in vitro by exposure to superoxide anions and that ascorbate protects against this effect. Also, a putative high pro-oxidant state in vivo, as indicated by low tissue ascorbate levels, resulted in a significant decrease in NT which an antioxidant intake normalized. These results taken together suggest that NT is sensitive to superoxide anion and that it may be a good marker of a pro-oxidant state in humans.