Showing papers in "Free Radical Research in 2010"
TL;DR: The generation of ROS within tumour cells, their detoxification, their cellular effects, as well as the major signalling cascades they utilize are discussed, but also an outlook on their modulation in therapeutics is provided.
Abstract: Elevated rates of reactive oxygen species (ROS) have been detected in almost all cancers, where they promote many aspects of tumour development and progression. However, tumour cells also express increased levels of antioxidant proteins to detoxify from ROS, suggesting that a delicate balance of intracellular ROS levels is required for cancer cell function. Further, the radical generated, the location of its generation, as well as the local concentration is important for the cellular functions of ROS in cancer. A challenge for novel therapeutic strategies will be the fine tuning of intracellular ROS signalling to effectively deprive cells from ROS-induced tumour promoting events, towards tipping the balance to ROS-induced apoptotic signalling. Alternatively, therapeutic antioxidants may prevent early events in tumour development, where ROS are important. However, to effectively target cancer cells specific ROS-sensing signalling pathways that mediate the diverse stress-regulated cellular functions need to be identified. This review discusses the generation of ROS within tumour cells, their detoxification, their cellular effects, as well as the major signalling cascades they utilize, but also provides an outlook on their modulation in therapeutics.
2,625 citations
TL;DR: New advances regarding apoptosis induction, survival/proliferation processes and autophagy regulated by 4-hydroxynonenal, a major product of omega-6 fatty acid peroxidation, in relationship with detoxication mechanisms are related.
Abstract: Oxidative stress and resulting lipid peroxidation is involved in various and numerous pathological states including inflammation, atherosclerosis, neurodegenerative diseases and cancer. This review is focused on recent advances concerning the formation, metabolism and reactivity towards macromolecules of lipid peroxidation breakdown products, some of which being considered as ‘second messengers’ of oxidative stress. This review relates also new advances regarding apoptosis induction, survival/proliferation processes and autophagy regulated by 4-hydroxynonenal, a major product of omega-6 fatty acid peroxidation, in relationship with detoxication mechanisms. The use of these lipid peroxidation products as oxidative stress/lipid peroxidation biomarkers is also addressed.
444 citations
TL;DR: A comprehensive review of the basic characteristics of DCFH2 and the present views of the mechanisms of its fluorescence formation are discussed to underline its advantages and disadvantages in ROS detection as well as for the methodological considerations that arise during analysis.
Abstract: Reactive oxygen species (ROS) are critically important chemical intermediates in biological studies, due to their multiple physiologically essential functions and their often pathologically deleterious effects. Consequently, it is vital that their presence in biological samples has to be quantifiable. However, their high activity, very short life span and extremely low concentrations make ROS measurement a scientifically challenging subject for researchers. One of the widespread methods for ROS detection, based on the oxidation of the non-fluorescent probe 2',7'-dichlorodihydrofluorescein (DCFH(2)) to yield the highly fluorescent 2',7'-dichlorofluorescein (DCF), was developed more than 40 years ago. However, from its initial application, argumentative questions have arisen regarding its action mechanisms, reaction principles and especially its specificity. Herein, the authors attempt to undertake a comprehensive review: to describe the basic characteristics of DCFH(2); to discuss the present views of the mechanisms of its fluorescence formation; to summarize the fluorescence formation interferents; to outline its application in biological research; and to underline its advantages and disadvantages in ROS detection as well as for the methodological considerations that arise during analysis.
428 citations
TL;DR: The results indicate that oxidative stress and elevated levels of oxidatively altered biomolecules are important intermediate endpoints that may be useful markers in hazard characterization of particulates.
Abstract: Particulates are small particles of solid or liquid suspended in liquid or air. In vitro studies show that particles generate reactive oxygen species, deplete endogenous antioxidants, alter mitocho...
401 citations
TL;DR: Striking evidences implicating LPO in foetal vascular dysfunction occurring in pre-eclampsia, in renal and liver diseases, as well as their role as cause and consequence to cancer development are addressed.
Abstract: Lipid peroxidation (LPO) product accumulation in human tissues is a major cause of tissular and cellular dysfunction that plays a major role in ageing and most age-related and oxidative stress-related diseases. The current evidence for the implication of LPO in pathological processes is discussed in this review. New data and literature review are provided evaluating the role of LPO in the pathophysiology of ageing and classically oxidative stress-linked diseases, such as neurodegenerative diseases, diabetes and atherosclerosis (the main cause of cardiovascular complications). Striking evidences implicating LPO in foetal vascular dysfunction occurring in pre-eclampsia, in renal and liver diseases, as well as their role as cause and consequence to cancer development are addressed.
379 citations
TL;DR: This review summarizes currently available data regarding the protective role of hydrogen, provides an outline of recent advances in research on the use of hydrogen as a therapeutic medical gas in diverse models of disease and discusses the feasibility of hydrogenAs a therapeutic strategy.
Abstract: Recent basic and clinical research has revealed that hydrogen is an important physiological regulatory factor with antioxidant, anti-inflammatory and anti-apoptotic protective effects on cells and organs. Therapeutic hydrogen has been applied by different delivery methods including straightforward inhalation, drinking hydrogen dissolved in water and injection with hydrogen-saturated saline. This review summarizes currently available data regarding the protective role of hydrogen, provides an outline of recent advances in research on the use of hydrogen as a therapeutic medical gas in diverse models of disease and discusses the feasibility of hydrogen as a therapeutic strategy. It is not an overstatement to say that hydrogen's impact on therapeutic and preventive medicine could be enormous in the future.
271 citations
TL;DR: Nrf2 emerges as a key regulator in oxidative stress-mediated diseases and Nrf2 silencing can open avenues in cancer treatment, according to a review of its role as a control point in oxidative Stress-induced cellular dysfunctions including chronic inflammatory diseases.
Abstract: Nrf2, a redox sensitive transcription factor, plays a pivotal role in redox homeostasis during oxidative stress. Nrf2 is sequestered in cytosol by an inhibitory protein Keap1 which causes its proteasomal degradation. In response to electrophilic and oxidative stress, Nrf2 is activated, translocates to nucleus, binds to antioxidant response element (ARE), thus upregulates a battery of antioxidant and detoxifying genes. This function of Nrf2 can be significant in the treatment of diseases, such as cancer, neurodegenerative, cardiovascular and pulmonary complications, where oxidative stress causes Nrf2 derangement. Nrf2 upregulating potential of phytochemicals has been explored, in facilitating cure for various ailments while, in cancer cells, Nrf2 upregulation causes chemoresistance. Therefore, Nrf2 emerges as a key regulator in oxidative stress-mediated diseases and Nrf2 silencing can open avenues in cancer treatment. This review summarizes Nrf2-ARE stress response mechanism and its role as a control point in oxidative stress-induced cellular dysfunctions including chronic inflammatory diseases.
264 citations
TL;DR: The search for new antioxidants of herbal origin, modification of tocopherols and their use in combination with selenium and properties of two promising groups of synthetic antioxidants: derivatives of stobadine and derivatives of 1,4-dihydropyridine are presented.
Abstract: The current understanding of the complex role of ROS in the organism and pathological sequelae of oxidative stress points to the necessity of comprehensive studies of antioxidant reactivities and interactions with cellular constituents. Studies of antioxidants performed within the COST B-35 action has concerned the search for new natural antioxidants, synthesis of new antioxidant compounds and evaluation and elucidation of mechanisms of action of both natural and synthetic antioxidants. Representative studies presented in the review concern antioxidant properties of various kinds of tea, the search for new antioxidants of herbal origin, modification of tocopherols and their use in combination with selenium and properties of two promising groups of synthetic antioxidants: derivatives of stobadine and derivatives of 1,4-dihydropyridine.
239 citations
TL;DR: The focus is on analysis of oxysterols, F2-isoprostanes and oxidized phospholipids by gas chromatography or liquid chromatography mass spectrometry techniques and immunoassays for the detection of 4-hydroxynonenal.
Abstract: Lipid peroxidation is recognized to be an important contributor to many chronic diseases, especially those of an inflammatory pathology. In addition to their value as markers of oxidative damage, lipid peroxidation products have also been shown to have a wide variety of biological and cell signalling effects. In view of this, accurate and sensitive methods for the measurement of lipid peroxidation products are essential. Although some assays have been described for many years, improvements in protocols are continually being reported and, with recent advances in instrumentation and technology, highly specialized and informative techniques are increasingly used. This article gives an overview of the most currently used methods and then addresses the recent advances in some specific approaches. The focus is on analysis of oxysterols, F(2)-isoprostanes and oxidized phospholipids by gas chromatography or liquid chromatography mass spectrometry techniques and immunoassays for the detection of 4-hydroxynonenal.
140 citations
TL;DR: Results indicate that APAP overdose caused hepatic injury due to its metabolism to hepatotoxic NAPQI (N-acetyl-p-benzoquinone imine), usually catalysed by CYP2E1, and via the direct activation of JNK-dependent cell death pathway.
Abstract: The present study was carried out to investigate whether taurine plays any beneficial role in acetaminophen (APAP)-induced acute hepatotoxicity. APAP exposure increased the plasma levels of ALT, ALP, LDH, TNF-alpha and NO production. Moreover, APAP treatment reduced the glutathione level and antioxidant enzyme activities, increased lipid peroxidation and caused hepatic DNA fragmentation which ultimately leads to cellular necrosis. Also, incubation of hepatocytes with APAP reduced cell viability, enhanced ROS generation and increased CYP2E1 activity. APAP overdose caused injury in the hepatic tissue and hepatocytes via the upregulation of CYP2E1 and JNK. Taurine treatment was effective in counteracting APAP-induced hepatic damages, oxidative stress and cellular necrosis. Results indicate that APAP overdose caused hepatic injury due to its metabolism to hepatotoxic NAPQI (N-acetyl-p-benzoquinone imine), usually catalysed by CYP2E1, and via the direct activation of JNK-dependent cell death pathway. Taurine possesses prophylactic as well as therapeutic potentials against APAP-induced hepatic injury.
140 citations
TL;DR: This mini-review shows shortcomings of TAC assays and points of concern that should be considered when performing and interpreting results of such assays.
Abstract: The 'Total antioxidant capacity' (TAC) is a parameter frequently used for characterization of food products and of the antioxidant status of the body. This mini-review shows shortcomings of TAC assays and points of concern that should be considered when performing and interpreting results of such assays. The term TAC is not optimal since the assay measures only part of antioxidant capacity, usually excluding enzymatic activities. Antioxidant and oxidant-regenerating enzymes in blood cells and the blood vessel wall have a profound impact on the antioxidant properties of blood plasma, which is not reflected in the in vitro assays of isolated plasma. The term 'Non-enzymatic antioxidant capacity' (NEAC) is suggested as more relevant than TAC. NEAC is estimated by various methods, which yield different values and results obtained using different methods do not always show satisfactory correlation. One reason for the discrepancy of results is the use of different oxidants in NEAC assays. The use of hydroxyl radical as the oxidant is not recommended in view of the high and non-specific reactivity of this species.
TL;DR: The protection of mtDNA from glucose-induced oxidative damage is one of the plausible mechanisms by which MnSOD ameliorates the development of diabetic retinopathy.
Abstract: Retinal mitochondria become dysfunctional in diabetes and the production of superoxide radicals is increased; over-expression of MnSOD abrogates mitochondrial dysfunction and prevents the development of diabetic retinopathy. The mitochondrial DNA (mtDNA) is particularly prone to oxidative damage. The aim of this study is to examine the role of MnSOD in the maintenance of mtDNA. The effect of MnSOD mimic, MnTBAP or over-expression of MnSOD on glucose-induced alterations in mtDNA homeostasis and its functional consequence was determined in retinal endothelial cells. Exposure of retinal endothelial cells to high glucose increased mtDNA damage and compromised the DNA repair machinery. The gene expressions of mitochondrial-encoded proteins of the electron transport chain complexes were decreased. Inhibition of superoxide radicals by either MnTBAP or by over-expression of MnSOD prevented mtDNA damage and protected mitochondrial-encoded genes. Thus, the protection of mtDNA from glucose-induced oxidative damage is one of the plausible mechanisms by which MnSOD ameliorates the development of diabetic retinopathy.
TL;DR: The involvement of MT in the protection of DNA against oxidative stress is discussed and its role in essential trace element homeostasis and in metal detoxification is discussed.
Abstract: Metallothioneins (MTs) are a family of low molecular weight proteins with a high cysteine and metal ion content. They are found in most cells and tissues and can be induced by a number of substances, including various forms of oxidative stress. MTs play a central role in essential trace element homeostasis and in metal detoxification. Because of their peculiar structure, characterized by a large content of thiol groups, MTs also act as a potent antioxidant by protecting against various injuries resulting from reactive oxygen (ROS) or nitrogen species (RNS). In this review, the involvement of MT in the protection of DNA against oxidative stress is discussed.
TL;DR: Altered expression of the Bcl-2 family of proteins, inhibition of NF-κB activation and over-expression of caspases and survivin provide compelling evidence that azadirachtin and nimbolide induce a shift of balance toward a pro-apoptotic phenotype.
Abstract: Limonoids from the neem tree (Azadirachta indica) have attracted considerable research attention in recent years owing to their potent antioxidant and anti-proliferative effects. The present study was designed to investigate the cellular and molecular mechanisms by which azadirachtin and nimbolide exert cytotoxic effects in the human cervical cancer (HeLa) cell line. Both azadirachtin and nimbolide significantly suppressed the viability of HeLa cells in a dose-dependent manner by inducing cell cycle arrest at G0/G1 phase accompanied by p53-dependent p21 accumulation and down-regulation of the cell cycle regulatory proteins cyclin B, cyclin D1 and PCNA. Characteristic changes in nuclear morphology, presence of a subdiploid peak and annexin-V staining pointed to apoptosis as the mode of cell death. Increased generation of reactive oxygen species with decline in the mitochondrial transmembrane potential and release of cytochrome c confirmed that the neem limonoids transduced the apoptotic signal via ...
TL;DR: In this article, a significant load of potentially pathogenic bacteria (> 10(6) cfu/mL) was cultured from the sputum of 17 (15%) subjects with stable asthma and was associated with higher total cell counts, proportion and number of neutrophils.
Abstract: Potential bacterial pathogens are found in the airways in several diseases that are associated with neutrophilic inflammation. The aim of this study was to characterize subjects with stable asthma, with no symptoms of respiratory infection, to assess whether key potentially pathogenic bacteria were present in significant quantities in the airways and to correlate this with the pattern of airway inflammation and oxidative stress. Subjects with stable asthma (n = 115) and healthy controls (n = 8) underwent clinical assessment, including hypertonic saline challenge combined with sputum induction. A significant load of potentially pathogenic bacteria (> 10(6) cfu/mL) was cultured from the sputum of 17 (15%) subjects with stable asthma and was associated with higher total cell counts, proportion and number of neutrophils, sputum IL-8 and 8-isoprostane concentrations. The role of bacteria in potentiating neutrophilic asthma warrants further investigation. Therapies such as antibiotic and antioxidant treatment may be most effective in this sub-group of patients.
TL;DR: It is demonstrated that treating cells with hydrogen before irradiation could significantly inhibit ionizing irradiation(IR)-induced Human Lymphocyte AHH-1 cells apoptosis and increase cells viability in vitro.
Abstract: It has been demonstrated that hydrogen can selectively reduce hydroxyl and peroxynitrite in vitro. Since most of the ionizing radiation-induced cellular damage is caused by hydroxyl radicals, this study was designed to test the hypothesis that hydrogen may be an effective radioprotective agent. This paper demonstrates that treating cells with hydrogen before irradiation could significantly inhibit ionizing irradiation(IR)-induced Human Lymphocyte AHH-1 cells apoptosis and increase cells viability in vitro. This paper also shows that hydrogen can protect gastrointestinal endothelia from radiation-induced injury, decrease plasma malondialdehyde (MDA) intestinal 8-hydroxydeoxyguanosine (8-OHDG) levels and increase plasma endogenous antioxidants in vivo. It is suggested that hydrogen has a potential as an effective and safe radioprotective agent.
TL;DR: In humans, EPA and DHA reduce in vivo oxidant stress as measured in human plasma and urine, which shows that Omega-3 fatty acids protect against cardiovascular disease and increase lipid peroxidation.
Abstract: Omega-3 ( ω 3) fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), protect against cardiovascular disease. Despite these benefi ts, concern remains that ω 3 fatty acids may increase lipid peroxidation. It has previously been shown that urinary F 2 -isoprostanes (F 2 -IsoPs) were reduced following ω 3 fatty acid supplementation in humans. It is now determined whether EPA or DHA supplementation affects plasma F 2 -IsoPs. In two 6-week placebo-controlled interventions, Study A: overweight, dyslipidaemic men; and Study B: treated-hypertensive Type 2 diabetic, patients were randomized to 4 g daily EPA, DHA. Post-intervention plasma F 2 -IsoPs were signifi cantly reduced by EPA (24% in Study A, 19% in Study B) and by DHA (14% in Study A, 23% in Study B) relative to the olive oil group. The fall in plasma F 2 -IsoPs was not altered in analyses that corrected for changes in plasma arachidonic acid, which was reduced with EPA and DHA supplementation. Neither F 3 - nor F 4 -IsoPs were observed in plasma in both studies. These results show that in humans, EPA and DHA reduce in vivo oxidant stress as measured in human plasma and urine.
TL;DR: This study presents the latest research findings on NRX and its related molecules, and explains how a thioredoxin-related protein, nucleoredoxin, governs ROS-stimulated Wnt signalling in a temporal manner.
Abstract: Numerous studies indicate that reactive oxygen species (ROS) are not merely cellular by-products of respiration, but are able to modulate various signalling pathways and play certain physiological roles Recent studies have revealed the importance of translating ROS-generation to activation/suppression of specific signalling pathways The Wnt signalling pathway, which is essential for early development and stem cell maintenance, is also regulated by ROS A thioredoxin-related protein, nucleoredoxin (NRX), governs ROS-stimulated Wnt signalling in a temporal manner NRX usually interacts with Dishevelled (Dvl), an essential adaptor protein for Wnt signalling, and blocks the activation of the Wnt pathway Oxidative stress causes dissociation of NRX from Dvl, which enables Dvl to activate the downstream Wnt signalling pathway This study also presents the latest research findings on NRX and its related molecules
TL;DR: The findings indicate that the antioxidant activity of arbutin may have been under-estimated and suggest that it acts as a potent antioxidant in the skin.
Abstract: Arbutin, a practically used skin-lightening agent, has been reported to possess a weak antioxidant activity compared to that of its precursor, hydroquinone. However, its antioxidant activity has not been systematically evaluated. Hence, this study reassessed its activity using five assay systems. Assays were first performed using model radicals, DPPH radical and ABTS•+. Arbutin showed weak DPPH radical-scavenging activity compared to that of hydroquinone, but showed strong ABTS•+-scavenging activity. Its activity by ORAC assay was then evaluated using a physiologically relevant peroxyl radical. Arbutin exerted weak but long-lasting radical-scavenging activity and showed totally the same antioxidant activity as that of hydroquinone. Finally, it was shown that, in two cell-based antioxidant assays using erythrocytes and skin fibroblasts, arbutin exerted strong antioxidant activity comparable or even superior to that of hydroquinone. These findings indicate that the antioxidant activity of arbutin ma...
TL;DR: Quercetin supplementation over 12 weeks in doses of 500 mg or 1000 mg/day significantly increased plasma quercet in levels, but had no influence on several measures of oxidative stress and antioxidant capacity.
Abstract: This study measured the influence of ingesting quercetin on plasma measures for oxidative stress and antioxidant capacity. Male and female subjects (n = 1002) varying in age (18-85 years) and body mass index (BMI) (16.7-52.7 kg/m(2)) were studied. Subjects were randomized to one of three groups using double-blinded methods: placebo, 500 mg or 1000 mg quercetin/day with 125 mg or 250 mg vitamin C/day, respectively. Pre- and post-study fasting blood samples show that plasma quercetin increased in a dose-responsive manner. The pattern of change in plasma F(2)-isoprostanes, oxidized low density lipoprotein, reduced glutathione, ferric reducing ability of plasma (FRAP) and oxygen radical absorbance capacity (ORAC) did not differ between supplementation groups or after adjustment for gender, age, BMI and disease status. In summary, quercetin supplementation over 12 weeks in doses of 500 mg or 1000 mg/day significantly increased plasma quercetin levels, but had no influence on several measures of oxidative stress and antioxidant capacity.
TL;DR: The data demonstrate that oxidative stress may cause degradation of phospholipids by oxidation, in particular CL; resulting in mitochondrial dysfunction.
Abstract: The aim of this study was to investigate the effect of oxidative stress on mitochondrial phospholipids. In this context, this study investigated (i) the content of phosphatidylethanolamine (PE), phosphatidylcholine (PC) and cardiolipin (CL), (ii) the correlation of CL degradation with mitochondrial function and (iii) the correlation of CL degradation and CL oxidation. Oxidative stress induced by iron/ascorbate caused a dramatic decrease of these phospholipids, in which CL was the most sensitive phospholipid. Even moderate oxidative stress by hypoxia/reoxygenation caused a decrease in CL that was parallelled by a decrease in active respiration of isolated rat heart mitochondria. The relation between oxidative stress, CL degradation and CL oxidation was studied by in vitro treatment of commercially available CL with superoxide anion radicals and H2O2. The degradation of CL was mediated by H2O2 and required the presence of cytochrome c. Other peroxidases such as horse radish peroxidase and glutathione peroxidase had no effect. Cytochrome c in the presence of H2O2 caused CL oxidation. The data demonstrate that oxidative stress may cause degradation of phospholipids by oxidation, in particular CL; resulting in mitochondrial dysfunction.
TL;DR: The results indicate that methyleugenol could be useful for the treatment of ischemia/inflammation-related diseases.
Abstract: The present study tested the cytoprotective effect of methyleugenol in an in vivo ischemia model (i.e. middle cerebral artery occlusion (MCAO) for 1.5 h and subsequent reperfusion for 24 h) and further investigated its mechanism of action in in vitro cerebral ischemic models. When applied shortly after reperfusion, methyleugenol largely reduced cerebral ischemic injury. Methyleugenol decreased the caspase-3 activation and death of cultured cerebral cortical neurons caused by oxygen-glucose deprivation (OGD) for 1 h and subsequent re-oxygenation for 24 h. Methyleugenol markedly reduced superoxide generation in the ischemic brain and decreased the intracellular oxidative stress caused by OGD/re-oxygenation. It was found that methyleugenol elevated the activities of superoxide dismutase and catalase. Further, methyleugenol inhibited the production of nitric oxide and decreased the protein expression of inducible nitric oxide synthase. Methyleugenol down-regulated the production of pro-inflammatory cytokines in the ischemic brain as well as in immunostimulated mixed glial cells. The results indicate that methyleugenol could be useful for the treatment of ischemia/inflammation-related diseases.
University of Hohenheim1, University of Eastern Finland2, University of Turin3, Spanish National Research Council4, University of Barcelona5, University of Bucharest6, Otto-von-Guericke University Magdeburg7, University of Strathclyde8, University of Valencia9, Carol Davila University of Medicine and Pharmacy10, Medical University of Białystok11, Medical University of Graz12, Strathclyde Institute of Pharmacy and Biomedical Sciences13
TL;DR: It is concluded that measurement of malondialdehyde by HPLC has good analytical validity for inter-laboratory studies on lipid peroxidation in human EDTA-plasma samples, although it is acknowledged that this may not translate to biological validity.
Abstract: Lipid peroxidation products like malondialdehyde, 4-hydroxynonenal and F(2)-isoprostanes are widely used as markers of oxidative stress in vitro and in vivo. This study reports the results of a multi-laboratory validation study by COST Action B35 to assess inter-laboratory and intra-laboratory variation in the measurement of lipid peroxidation. Human plasma samples were exposed to UVA irradiation at different doses (0, 15 J, 20 J), encoded and shipped to 15 laboratories, where analyses of malondialdehyde, 4-hydroxynonenal and isoprostanes were conducted. The results demonstrate a low within-day-variation and a good correlation of results observed on two different days. However, high coefficients of variation were observed between the laboratories. Malondialdehyde determined by HPLC was found to be the most sensitive and reproducible lipid peroxidation product in plasma upon UVA treatment. It is concluded that measurement of malondialdehyde by HPLC has good analytical validity for inter-laboratory studies on lipid peroxidation in human EDTA-plasma samples, although it is acknowledged that this may not translate to biological validity.
TL;DR: The results obtained suggest that, similar to PQ, Zn induced neurodegeneration via alterations in oxidative stress and expression of the above-mentioned genes, however, the effect of Zn+PQ was only slightly higher than that of alone, indicating that probably Zn and PQ follow some different molecular events leading to neurodegenersation.
Abstract: Oxidative stress is implicated in Parkinson's disease (PD). Metallothioneins (MT), cytochrome P450 IIE1 (CYP2E1) and glutathione S-transferases alpha4-4 (GSTA4-4) are involved in oxidative stress-mediated damage. Altered dopamine transporter (DAT) and vesicular monoamine transporter-2 (VMAT-2) are also documented in PD. The present study was undertaken to investigate the effect of Zn and PQ co-exposure on neurodegeneration in rats. A significant reduction was observed in spontaneous locomotor activity (SLA), striatal dopamine (DA) levels, tyrosine hydroxylase (TH) immunoreactivity, glutathione reductase (GR) and catalase activity along with increased lipid peroxidation (LPO) and glutathione peroxidase (GPx) activity after Zn and/or PQ exposure. Zn and/or PQ exposure increased gene expression of DAT, CYP2E1, GSTA4-4, MT-I and MT-II, but reduced the expression of VMAT-2. Protein expression analysis of TH, VMAT-2 and DAT showed results similar to those obtained with gene expression study. Zn and PQ c...
TL;DR: The data suggest that MGO stimulates superoxide production from mitochondria and partially stimulates nitric oxide synthase in human endothelial cells.
Abstract: Methylglyoxal (MGO) is a non-enzymatic metabolite in the glycolytic pathway and its concentration in blood and tissues is elevated in diabetes and renal failure. MGO induces tissue injuries via ROS; however, the mechanism remains to be clarified. The present study examined the harmful actions of MGO. Human aortic endothelial cells were assessed under real-time fluorescent microscopy with continuous superfusion. Increases in intracellular ROS were measured with fluorescent indicator, 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate acetyl ester (DCFH-DA). The addition of MGO rapidly increased the ROS in a dose-dependent manner. The increment of DCF was entirely abolished by pre-treatment with superoxide anion scavenger and membrane-permeable catalase, indicating that MGO induces superoxide production. The increment was completely inhibited by 2-thenoyltrifluoroacetone or carbonyl cyanide 3-chlorophenylhydrazone and partially inhibited by N-methyl-L-arginine. These data suggest that MGO stimulates superoxide production from mitochondria and partially stimulates nitric oxide synthase in human endothelial cells.
TL;DR: It is suggested that ROS levels may be used as an early indicator of sperm count and quality decreases which result from chronic toxicity.
Abstract: Bisphenol A (BPA) and diethylstilbestrol (DES) have been reported to cause sperm toxicity. To identify an earlier marker of toxicity of environmental substances or food additives, this study determined whether the levels of reactive oxygen species (ROS) in sperms could serve as indices for the prediction of sperm toxicity and quality. Male Wistar rats were given drinking water containing various doses of BPA or DES for 8 weeks. Some rats were treated with 0.45% N-acetyl cysteine (NAC) for 2 days prior to the administration of DES or BPA. Administration of BPA or DES to rats for 1 week dose-dependently increased the production of ROS, even at doses and time points which had no effect on sperm motility. 4-Hydroxy-2-nonenal modified proteins increased in sperms 8 weeks after BPA or DES treatment. NAC reversed oxidative stress and prevented the loss of sperm function in the DES or BPA-treated group. During observation, changes in the sperm motility, sperm count and morphology were not correlated to the increase in ROS levels. These results suggest that ROS levels may be used as an early indicator of sperm count and quality decreases which result from chronic toxicity.
TL;DR: New findings that point to the nuclear reduced status as an environment that induces heterochromatin formation are summarized and appear as a reversible physiological mechanism able to regulate DNA compaction, cell cycle and DNA repair.
Abstract: Cells with high proliferation rate have high glutathione levels. This typical feature of cancer cells is viewed usually as a defence mechanism against ionizing radiation or chemotherapy. Efforts have been made in order to decrease cellular glutathione levels in tumours as a necessary pre-treatment for cancer therapy. However, very few reports have considered cellular glutathione as a physiological tool for cells to proliferate and that most of this high glutathione levels were located in the nucleus. The role of nuclear glutathione in cell physiology has become more important in the last years. This review summarizes new findings that point to the nuclear reduced status as an environment that induces heterochromatin formation. Glutathionylation and oxidation of nuclear proteins appear as a reversible physiological mechanism able to regulate DNA compaction, cell cycle and DNA repair.
TL;DR: In this article, the effect of morin's anti-oxidant effect on RS-induced NF-kappaB activation via reduced DNA binding activity, I kappaB alpha phosphorylation and p65/p50 nuclear translocation was investigated.
Abstract: Morin is a flavone that has anti-inflammatory effects through a mechanism that is not well understood. Based on the extreme sensitive nature of the transcription factor, NF-kB to redox change, it is postulated that morin's anti-NF-kappaB activation likely depends on its ability to scavenge excessive reactive species [RS]. The present study assessed the extent of morin's ability to modulate RS-induced NF-kappaB activation through its scavenging activity. Results indicate that morin neutralized RS in vitro and inhibited t-BHP-induced RS generation. It also examined morin for suppressed redox-sensitive transcription factor NF-kappaB activation via reduced DNA binding activity, I kappaB alpha phosphorylation and p65/p50 nuclear translocation. The more important finding was that suppression of the NF-kappaB cascade by morin was modulated through the ERK and p38 MAPKs signal transduction pathways in endothelial cells. As a consequence, morin's anti-oxidant effect extended expression level of NF-kappaB dependent pro-inflammatory genes, thereby reducing COX-2, iNOS and 5-LOX. The data indicate that morin has strong anti-oxidative power against RS-induced NF-kappaB modulation through the ERK and p38 MAPKs signalling pathways by its RS scavenging activity. The significance of the current study is the new revelation that morin may have potential as an effective anti-inflammatory therapeutic agent.
TL;DR: 5-LO plays a critical role in HNE-induced ROS generation in murine macrophages through activation of NADPH oxidase, as well as in J774A.1 cells treated with a 5-lo inhibitor, MK886 or 5-LO siRNA.
Abstract: 4-Hydroxynonenal (HNE) mediates oxidative stress-linked pathological processes; however, its role in the generation of reactive oxygen species (ROS) in macrophages is still unclear. Thus, this study investigated the sources and mechanisms of ROS generation in macrophages stimulated with HNE. Exposure of J774A.1 cells to HNE showed an increased production of ROS, which was attenuated by NADPH oxidase as well as 5-lipoxygenase (5-LO) inhibitors. Linked to these results, HNE increased membrane translocation of p47phox promoting NADPH oxidase activity, which was attenuated in peritoneal macrophages from 5-LO-deficient mice as well as in J774A.1 cells treated with a 5-LO inhibitor, MK886 or 5-LO siRNA. In contrast, HNE-enhanced 5-LO activity was not affected by inhibition of NADPH oxidase. Furthermore, leukotriene B(4), 5-LO metabolite, was found to enhance NADPH oxidase activity in macrophages. Altogether, these results suggest that 5-LO plays a critical role in HNE-induced ROS generation in murine macrophages through activation of NADPH oxidase.
TL;DR: It appears that variants in MnSOD, CAT or GPX1 have an influence on HCC risk in this cohort, and it is possible that cumulative defects in protection from oxidative stress may result in increased risk of liver cancer in the Moroccan population.
Abstract: Reactive oxygen species have been related to the aetiology of cancer as they are known to be mitogenic and therefore capable of tumour promotion. The aim of this study was to assess the role of common variation in three polymorphic genes (MnSOD Ala-9Val, GPX1 Pro198Leu and CAT −262 C > T) coding for antioxidant defence enzymes in modulating individual susceptibility to hepatocellular carcinoma (HCC) using a case-control study (cases = 96 and controls = 222). PCR-RFLP and sequencing methods were used to determine the genotype. Overall, there were no associations between genotypes GPX1 and HCC risk (OR, 1.16; 95% CI, 0.56–2.42; p = 0.685). The MnSOD Ala/Ala and CAT TT genotypes were more frequent in HCC than in control (p = 0.001 and p = 0.072, respectively). Further analyses stratified by gender or HCV infection revealed that men and HCV-infected patients carrying CAT TT genotype had a higher risk to develop HCC when compared with controls (OR = 15.94; 95% CI, 3.48–72.92; p < 0.000001 and 12.01; 95...