Cancer-preventive isothiocyanates: measurement of human exposure and mechanism of action

Numerous studies in rodents have documented the cancer-preventive activity of a significant number of isothiocyanates (ITCs), the majority of which occur in plants, especially in cruciferous vegetables. Dietary ITCs may play an important role in the prevention of human cancers. Several recent epidemiological studies have already shown that dietary consumption of ITCs inversely correlates with the risk of developing lung, breast and colon cancers. ITCs are principally metabolized through the mercapturic acid pathway in vivo, giving rise to N-acetylcysteine conjugates, which are excreted in the urine. Analytical methods have been developed to allow detection of ITCs and their metabolites formed in the mercapturic acid pathway. Studies show that total urinary level of ITC equivalent is an excellent biomarker of human exposure to ITCs. Moreover, these methods also have made it possible to learn the bioavailability of ITCs from cruciferous vegetables. ITCs possess multiple anticarcinogenic mechanisms, including inhibition of carcinogen-activating enzymes, induction of carcinogen-detoxifying enzymes, increase of apoptosis, arrest of cell cycle progression, as well as several other mechanisms that are not yet fully described. These mechanisms, which are discussed in detail in this review, illustrate the remarkable ability of ITCs to inhibit cancer development-effective against both developing and developed cancer cells.     

A meta-analysis of glucocorticoids as modulators of oxidative stress in vertebrates

Prolonged high secretion of glucocorticoids normally reflects a state of chronic stress, which has been associated with an increase in disease susceptibility and reduction in Darwinian fitness. Here, we hypothesize that an increase in oxidative stress accounts for the detrimental effects of prolonged high secretion of glucocorticoids. We performed a meta-analysis on studies where physiological stress was induced by administration of glucocorticoids to evaluate the magnitude of their effects on oxidative stress. Glucocorticoids have a significant effect on oxidative stress (Pearson r = 0.552), although this effect depends on the duration of treatment, and is larger in long-term experiments. Importantly, there was a significant effect on tissue, with brain and heart being the most and the least susceptible to GC-induced oxidative stress, respectively. Furthermore, effect size was larger (1) in studies using both sexes compared to males only, (2) when corticosterone rather than dexamethasone was administered and (3) in juveniles than in adults. These effects were not confounded by species, biochemical biomarker, or whether wild or laboratory animals were studied. In conclusion, our meta-analysis suggests that GC-induced oxidative stress could be a further mechanism underlying increases in disease susceptibility and decreases in Darwinian fitness observed under chronic stress.     

Novel selenoorganic compounds as modulators of oxidative stress in blood platelets

Many selenoorganic compounds play an important role in biochemical processes and act as antioxidants, enzyme inhibitors, or drugs. The effects of five new synthesized selenoorganic compounds (2-(5-chloro-2-pyridyl)-7-azabenzisoselenazol-3(2H)-one; 2-phenyl-7-azabenzisoselenazol-3(2H)-one; 2-(pyridyl)-7-azabenzisoselenazol-3(2H)-one; 7-azabenzisoselenazol-3(2H)-one; bis(2-aminophenyl) diselenide) on oxidative changes in human blood platelets and in plasma were studied in vitro and compared with those of ebselen, a well known antioxidant. Our studies demonstrated that bis(2-aminophenyl) diselenide has distinctly protective effects against oxidative stress in blood platelets and in plasma. It might have greater biological relevance and stronger pharmacological effects than ebselen.     

Polyamines as modulators of gene expression under oxidative stress in Escherichia coli

Activity of enzymes of polyamine synthesis and contents of their products increased in E. coli cells in response to oxidative stress caused by addition of hydrogen peroxide to an exponentially growing culture. Putrescine and spermidine added to the culture medium in physiological concentrations significantly increased expression of genes oxyR and katG responsible for defense against oxidative stress, whereas cadaverine had no effect. The role of polyamines as modulators of the gene expression was confirmed by experiments with an inhibitor of polyamine synthesis, 1,3-diaminopropane, which decreased the level of cell polyamines and thus abolished the ability of the cell to induce oxyR expression under oxidative stress. A genetic method gave similar results: under oxidative stress mutants with disorders in polyamine synthesis displayed a significantly decreased level of induction of the oxyR and katG genes, and this level was recovered on addition of putrescine. In the presence of inhibitors of DNA-gyrase, nalidixic acid and novobiocin, the oxyR expression depended on the extent of DNA supercoiling. Putrescine decreased the inhibitory effects of nalidixic acid and novobiocin, and this confirmed its properties of a stimulator of DNA supercoiling. Resistance to rifampicin was studied to exemplify the mutation rate under oxidative stress. Putrescine decreased twofold the level of mutations and increased the number of viable cells in the culture exposed to oxidative stress.     

Commentary: oxidative stress reconsidered

All definitions of the terms ‘oxidative stress’ and ‘antioxidants’ implicate that oxidants are just damaging. However, there is increasing evidence that reactive oxygen species (ROS) are not only toxic but that we need them for healthy life. This change in paradigm has been discussed at the third international symposium on ‘Nutrition, oxygen biology and medicine—micronutrients, exercise, energy and aging disorders’, of the Society for Free Radical Research France and the Oxygen Club of California on April 8–10, 2009 in Paris. The beneficial effect of a low to moderate concentration of oxidants produced during exercise was taken as most discussed example. In this case, ROS are required for normal force production in skeletal muscle, for the development of training-induced adaptation in endurance performance, as well as for the induction of endogenous defense systems. Taking antioxidants during training prevents adaptation. Although substantial progress on the understanding of the physiological functions of ROS was communicated at the meeting, it remained obvious that a lot of work is needed to fully understand the conditions and individual situations under which ROS are beneficial or detrimental.     

Cadmium stress: an oxidative challenge

At the cellular level, cadmium (Cd) induces both damaging and repair processes in which the cellular redox status plays a crucial role. Being not redox-active, Cd is unable to generate reactive oxygen species (ROS) directly, but Cd-induced oxidative stress is a common phenomenon observed in multiple studies. The current review gives an overview on Cd-induced ROS production and anti-oxidative defense in organisms under different Cd regimes. Moreover, the Cd-induced oxidative challenge is discussed with a focus on damage and signaling as downstream responses. Gathering these data, it was clear that oxidative stress related responses are affected during Cd stress, but the apparent discrepancies observed in between the different studies points towards the necessity to increase our knowledge on the spatial and temporal ROS signature under Cd stress. This information is essential in order to reveal the exact role of Cd-induced oxidative stress in the modulation of downstream responses under a diverse array of conditions.     

Ethanol-induced oxidative stress: basic knowledge

After a general introduction, the main pathways of ethanol metabolism (alcohol dehydrogenase, catalase, coupling of catalase with NADPH oxidase and microsomal ethanol-oxidizing system) are shortly reviewed. The cytochrome P₄₅₀ isoform (CYP2E1) specifically involved in ethanol oxidation is discussed. The acetaldehyde metabolism and the shift of the NAD/NADH ratio in the cellular environment (reductive stress) are stressed. The toxic effects of acetaldehyde are mentioned. The ethanol-induced oxidative stress: the increased MDA formation by incubated liver preparations, the absorption of conjugated dienes in mitochondrial and microsomal lipids and the decrease in the most unsaturated fatty acids in liver cell membranes are discussed. The formation of carbon-centered (1-hydroxyethyl) and oxygen-centered (hydroxyl) radicals during the metabolism of ethanol is considered: the generation of hydroxyethyl radicals, which occurs likely during the process of univalent reduction of dioxygen, is highlighted and is carried out by ferric cytochrome P₄₅₀ oxy-complex (P₄₅₀–Fe³⁺O₂^·−) formed during the reduction of heme-oxygen. The ethanol-induced lipid peroxidation has been evaluated, and it has been shown that plasma F₂-isoprostanes are increased in ethanol toxicity.     

Postprandial oxidative stress

Consumption of a meal containing oxidized and oxidizable lipids gives rise to an increased plasma concentration of lipid hydroperoxides, detectable by a sensitive chemiluminescence procedure. This is associated with increased susceptibility of LDL to oxidation, apparently due a structural perturbation at the particle surface brought about by lipid oxidation products. The postprandial modification of LDL is at least partially accounted for by an increase of LDL-, a subfraction containing lipid oxidation products where apoprotein-B-100 (apoB-100) is denatured. Consuming the meal with a suitable source of antioxidants, such as those found in red wine, minimizes this postprandial oxidative stress. The inhibition of peroxidation of lipids present in the meal during digestion is a possible mechanism for the observed protection of LDL. The in vivo oxidatively modified LDL- has numerous features that correspond to the atherogenic minimally modified LDL produced in vitro. These modified particles could account for a relevant link between nutrition and early biological processes that foster the development of atherosclerosis.     

Alcohol-induced oxidative stress

Alcohol-induced oxidative stress is linked to the metabolism of ethanol involving both microsomal and mitochondrial systems. Ethanol metabolism is directly involved in the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). These form an environment favourable to oxidative stress. Ethanol treatment results in the depletion of GSH levels and decreases antioxidant activity. It elevates malondialdehyde (MDA), hydroxyethyl radical (HER), and hydroxynonenal (HNE) protein adducts. These cause the modification of all biological structures and consequently result in serious malfunction of cells and tissues.     

Cytoprotective small molecule modulators of endoplasmic reticulum stress

Cellular health depends on the normal function of the endoplasmic reticulum (ER) to fold, assemble, and modify critical proteins to maintain viability. When the ER cannot process proteins effectively, a condition known as ER stress ensues. When this stress is excessive or prolonged, cell death via apoptotic pathways is triggered. Interestingly, most major diseases have been shown to be intimately linked to ER stress, including diabetes, stroke, neurodegeneration, and many cancers. Thus, controlling ER stress presents a significant strategy for drug development for these diseases. The goal of this review is to present various small molecules that alleviate ER stress with the intention that they may serve as useful starting points for therapeutic agent development.     

Mini-review: Biofilm responses to oxidative stress

Biofilms constitute the predominant microbial style of life in natural and engineered ecosystems. Facing harsh environmental conditions, microorganisms accumulate reactive oxygen species (ROS), potentially encountering a dangerous condition called oxidative stress. While high levels of oxidative stress are toxic, low levels act as a cue, triggering bacteria to activate effective scavenging mechanisms or to shift metabolic pathways. Although a complex and fragmentary picture results from current knowledge of the pathways activated in response to oxidative stress, three main responses are shown to be central: the existence of common regulators, the production of extracellular polymeric substances, and biofilm heterogeneity. An investigation into the mechanisms activated by biofilms in response to different oxidative stress levels could have important consequences from ecological and economic points of view, and could be exploited to propose alternative strategies to control microbial virulence and deterioration.     

The retina: oxidative stress and diabetes

A prominent and early feature of the retinopathy of diabetes mellitus is a diffuse increase in vascular permeability. As the disease develops, the development of frank macular oedema may result in vision loss. That reactive oxygen species production is likely to be elevated in the retina, and that certain regions of the retina are enriched in substrates for lipid peroxidation, may create an environment susceptible to oxidative damage. This may be more so in the diabetic retina, where hyperglycaemia may lead to elevated oxidant production by a number of mechanisms, including the production of oxidants by vascular endothelium and leukocytes. There is substantial evidence from animal and clinical studies for both impaired antioxidant defences and increased oxidative damage in the retinae of diabetic subjects that have been, in the case of animal studies, reversible with antioxidant supplementation. Whether oxidative damage has a causative role in the pathology of diabetic retinopathy, and thus whether antioxidants can prevent or correct any retinal damage, has not been established, nor has the specific nature of any damaging species been characterised.     

Methotrexate: pentose cycle and oxidative stress

The effect of methotrexate (MTX) and leucovorin (LCV) on pentose cycle enzymes and the activity of enzymes involved in enzyme defence mechanisms against ROS in HeLa cells, were studied. The effect of MTX was also investigated on the cellular levels of glutathione. MTX inhibited the activity of glucose-6-phosphate and 6-phosphogluconate dehydrogenases. The activities of glutathione reductase and γ-glutamylcysteine synthetase were also inhibited by the drug. No effect was observed on the activities of catalase, superoxide dismutase or transketolase. LCV had no effect on any of the enzymes studied. MTX decreased the cellular levels of glutathione (70 per cent), while the presence of LCV and glutamine did not interfere with the effect of MTX. The net results appear to show that the biological situation resulting from treatment with MTX leads to a reduction of effectiveness of the antioxidant enzyme defence system. Copyright © 1998 John Wiley & Sons, Ltd.     

The oxidative stress: endoplasmic reticulum stress axis in cadmium toxicity

Cadmium preferentially accumulates in the kidney, the major target for cadmium-related toxicity. Several underlying mechanisms are postulated, and reactive oxygen species (ROS) have been considered as crucial mediators for tissue injuries. In addition to oxidative stress, we recently disclosed that endoplasmic reticulum (ER) stress also plays a critical role. Cadmium causes ER stress in vitro and in vivo and mediates induction of apoptosis in target tissues. In this article, we describe a role for ER stress and involvement of particular branches of the unfolded protein response (UPR) in cadmium-triggered tissue injury, especially nephrotoxicity. We also discuss relationship between oxidative stress and ER stress, and involvement of selective ROS in the induction of pro-apoptotic branches of the UPR.     

Disulfide stress: a novel type of oxidative stress in acute pancreatitis

Glutathione oxidation and protein glutathionylation are considered hallmarks of oxidative stress in cells because they reflect thiol redox status in proteins. Our aims were to analyze the redox status of thiols and to identify mixed disulfides and targets of redox signaling in pancreas in experimental acute pancreatitis as a model of acute inflammation associated with glutathione depletion. Glutathione depletion in pancreas in acute pancreatitis is not associated with any increase in oxidized glutathione levels or protein glutathionylation. Cystine and homocystine levels as well as protein cysteinylation and γ-glutamyl cysteinylation markedly rose in pancreas after induction of pancreatitis. Protein cysteinylation was undetectable in pancreas under basal conditions. Targets of disulfide stress were identified by Western blotting, diagonal electrophoresis, and proteomic methods. Cysteinylated albumin was detected. Redox-sensitive PP2A and tyrosine protein phosphatase activities diminished in pancreatitis and this loss was abrogated by N-acetylcysteine. According to our findings, disulfide stress may be considered a specific type of oxidative stress in acute inflammation associated with protein cysteinylation and γ-glutamylcysteinylation and oxidation of the pair cysteine/cystine, but without glutathione oxidation or changes in protein glutathionylation. Two types of targets of disulfide stress were identified: redox buffers, such as ribonuclease inhibitor or albumin, and redox-signaling thiols, which include thioredoxin 1, APE1/Ref1, Keap1, tyrosine and serine/threonine phosphatases, and protein disulfide isomerase. These targets exhibit great relevance in DNA repair, cell proliferation, apoptosis, endoplasmic reticulum stress, and inflammatory response. Disulfide stress would be a specific mechanism of redox signaling independent of glutathione redox status involved in inflammation.