Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword?

The endoplasmic reticulum (ER) is a well-orchestrated protein-folding machine composed of protein chaperones, proteins that catalyze protein folding, and sensors that detect the presence of misfolded or unfolded proteins. A sensitive surveillance mechanism exists to prevent misfolded proteins from transiting the secretory pathway and ensures that persistently misfolded proteins are directed toward a degradative pathway. The unfolded protein response (UPR) is an intracellular signaling pathway that coordinates ER protein-folding demand with protein-folding capacity and is essential to adapt to homeostatic alterations that cause protein misfolding. These include changes in intraluminal calcium, altered glycosylation, nutrient deprivation, pathogen infection, expression of folding-defective proteins, and changes in redox status. The ER provides a unique oxidizing folding-environment that favors the formation of the disulfide bonds. Accumulating evidence suggests that protein folding and generation of reactive oxygen species (ROS) as a byproduct of protein oxidation in the ER are closely linked events. It has also become apparent that activation of the UPR on exposure to oxidative stress is an adaptive mechanism to preserve cell function and survival. Persistent oxidative stress and protein misfolding initiate apoptotic cascades and are now known to play predominant roles in the pathogenesis of multiple human diseases including diabetes, atherosclerosis, and neurodegenerative diseases.     

Does oxidative stress play a critical role in cardiovascular complications of kawasaki disease?

Abstract The aim of the present work was to evaluate the contribution of the different reactive oxidizing species to systemic oxidative stress in the whole blood of patients with Kawasaki disease (KD). This is a rare generalized systemic vasculitis typical of the early childhood characterized by inflammation and endothelial dysfunction with a high risk for cardiovascular fatal events. We found that, compared to age-matched healthy donors, blood from KD patients showed increased production of oxygen- and nitrogen-derived species as detected by electron paramagnetic resonance (EPR) spin probing with the cyclic hydroxylamine 1-hydroxy-3-carboxy-pyrrolidine. The (?)NO pathway involvement was also confirmed by the decreased concentrations of the endogenous (?)NO synthase inhibitor asymmetric dimethyl-arginine and the increased amounts of 3-nitrotyrosine in plasma. Further, increased plasma yields of the proinflammatory enzyme myeloperoxidase were also observed. The appearance of circulating red blood cell alterations typically associated with oxidative imbalance and premature aging (e.g., decrease of total thiol content, glycophorin A, and CD47 expression, as well as increase of phosphatidylserine externalization) has also been detected. Collectively, our observations lead to hypothesize that the simultaneous oxidative and nitrative stress occurrence in the blood of KD patients may play a pathogenetic role in the cardiovascular complications often associated with this rare disease. Antioxid. Redox Signal. 17, 1441-1446.     

Metabolic muscle damage and oxidative stress markers in an America’s Cup yachting crew

Activities of enzymes involved in muscle damage [creatine kinase (CK) and aspartate aminotransferase (AST)] and levels of malondialdehyde (MDA) as a marker of oxidative stress were monitored in the plasma of 27 members of an America’s Cup yachting crew. The preventive benefits of allopurinol on muscle damage were also tested. In racing period A, the crew was divided into two groups according to their tasks on board. Blood samples from all 27 sailors were obtained before the start of a 5-day fleet race, after the last race, and after the ten match races. In period B, crew members were divided at random into two groups. One group (13 participants) received 300 mg/day of allopurinol 3 h before racing. The other ten members received placebo. Blood samples were collected just before and after the second round of the Louis Vuitton Cup. All participants showed increased CK and AST activities after the racing period A. The increase in CK activity was highest in sailors involved in strenuous physical work. At the end of period A, plasma MDA levels were higher in all participants as compared with non-participant athletes. In period B, a significant decrease in CK activity, but not in AST, appeared among participants receiving allopurinol. Plasma MDA decreased in sailors treated with allopurinol, but this reduction did not reach statistical significance. America’s Cup is a sailing sport with high physical demands, as shown by the increase in muscle-damage markers. Treatment with allopurinol appeared to decrease the levels of muscle damage markers.     

Do bimanual isometric push efforts in humans stop as a consequence of postural muscle exhaustion?

The purpose of this study was to explore whether global efforts stop as a consequence of postural muscle exhaustion. To this end, seated adults were asked to exert 75% maximal voluntary contractions bimanual push efforts until exhaustion. A dynamometer was used to measure the horizontal force exerted on a bar (Fx) and a custom-designed force plate measured the antero-posterior displacement of the centre of pressure (Xp). Electromyograms were picked up by bipolar surface electrodes from the primum movens (serratus anterior) and four postural muscles (trapezius superior, erectores spinae, rectus abdominis, rectus femoris). Root mean square and mean power frequency were calculated over 2-s intervals and compared to corresponding Fx and Xp values. It was shown that the effort stops as a consequence of exhaustion of postural muscles (rectus abdominis and rectus femoris), and not of the primum movens. It is concluded that postural muscles make a major contribution to global efforts, in that they allow compliance to biomechanical requirements, that is, to preserve the distance between the centre of pressure and the centre of gravity, which must be proportional to the external force.     

The effects of running exercise on oxidative capacity and PGC-1α mRNA levels in the soleus muscle of rats with metabolic syndrome

Skeletal muscles in animals with metabolic syndrome exhibit reduced oxidative capacity. We investigated the effects of running exercise on fiber characteristics, oxidative capacity, and mRNA levels in the soleus muscles of rats with metabolic syndrome [SHR/NDmcr-cp (cp/cp); CP]. We divided 5-week-old CP rats into non-exercise (CP) and exercise (CP-Ex) groups. Wistar-Kyoto rats (WKY) were used as the control group. CP-Ex rats were permitted voluntary exercise on running wheels for 10 weeks. Triglyceride levels were higher and adiponectin levels lower in the CP and CP-Ex groups than in the WKY group. However, triglyceride levels were lower and adiponectin levels higher in the CP-Ex group than in the CP group. The soleus muscles in CP-Ex rats contained only high-oxidative type I fibers, whereas those in WKY and CP rats contained type I, IIA, and IIC fibers. Muscle succinate dehydrogenase (SDH) activity was higher in the CP-Ex group than in the CP group; there was no difference in SDH activity between the WKY and CP-Ex groups. Muscle proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA levels were higher in the CP-Ex group than in the CP group; there was no difference in PGC-1α mRNA levels between the WKY and CP-Ex groups. In CP-Ex rats, longer running distance was associated with increased muscle SDH activity and PGC-1α mRNA levels. We concluded that running exercise restored decreased muscle oxidative capacity and PGC-1α mRNA levels and improved hypertriglyceridemia in rats with metabolic syndrome.     

Urinary 8-hydroxy-2'-deoxyguanosine: a biomarker of environmental oxidative stress?

The oxidative stress plays an important role in certain pathologies, notably in carcinogenesis. Indeed, reactive oxygen species (ROS) can induce a variety of damage to DNA, including oxidized bases which will then be repaired and eliminated in urine. The 8-hydroxy-2'-deoxyguanosine (8-OHdG), the most frequent member of these oxidized bases, can be measured in DNA or in urine by various methods. The urinary measurement was used in several studies among subjects with occupational or environmental exposure. Diverse chemical or physical agents can indeed contribute to the increase of oxidative stress, although the latter has several origins. Our objective is to analyze through these studies the interest, the limits and the implementation of this biomarker. The majority of the studies reveal an increase of the concentration of 8-OHdG in urine in exposed subjects (polycyclic aromatic hydrocarbons, metals, ionizing radiation and other agents) compared with controls or according to exposure levels. The urinary concentration of 8-OHdG is subject to important inter and intra-individual variations. The biomonitoring studies have to take into account diverse confounding factors, which may have conflicting effects. Moreover the results strongly depend on the analytical method used. Thus other investigations are necessary to validate this biomarker and better know its sources of variability, its biological significance, its dose-response relationship and its kinetics after exposure to oxidative stress agents.     

Is somnambulism a distinct disorder of humans and not seen in non-human primates?

Though somnambulism (sleepwalking) is a well-recognized sleep disorder in humans, a biomedical literature search in Medline and Primate Literature bibliographic databases showed no publications on sleepwalking in non-human primates. From this finding, two inferences can be made. First is that somnambulism may be present in non-human primates; but due to limitations in expertise and methodological resources as well as narrow focus of research interest, until now researchers have not detected it in wild and/or captive conditions. Second, somnambulism does not exist in non-human primates including apes (chimpanzee, gorilla, orang-utan and gibbon); and thus, it is a unique behavioral disorder present only in humans. It is premature to conclude which of these two inferences is correct. In Jane Goodall's view, sleepwalking behavior is absent in chimpanzees. If further field observations can confirm Goodall's assertion that somnambulism is indeed absent in chimpanzees, it will be of evolutionary and medical interest to know why this parasomnic behavior became established in humans during the past 5.5 million years or so.     

PGC-1α mRNA level and oxidative capacity of the plantaris muscle in rats with metabolic syndrome, hypertension, and type 2 diabetes

We examined the fiber profiles and the mRNA levels of peroxisome proliferator-activated receptors (PPARα and PPARδ/β) and of the PPARγ coactivator-1α (PGC-1α) in the plantaris muscles of 15-week-old control (WR), metabolic syndrome (CP), hypertensive (SHR), and type 2 diabetic (GK) rats. The deep regions in the muscles of SHR and GK rats exhibited lower percentages of high-oxidative type I and IIA fibers and higher percentages of low-oxidative type IIB fibers compared with WR and CP rats. The surface regions in the muscles of CP, SHR, and GK rats exhibited lower percentages of high-oxidative type IIA fibers and higher percentages of low-oxidative type IIB fibers compared with WR rats. The muscles of SHR and GK rats had lower oxidative enzyme activity compared with WR rats. The muscles of SHR rats had the lowest PPARδ/β mRNA level. In addition, the muscles of SHR and GK rats had lower PGC-1α mRNA level compared with WR and CP rats. We concluded that the plantaris muscles of rats with hypertension and type 2 diabetes have lower oxidative capacity, which is associated with the decreased level of PGC-1α mRNA.     

In vivo detection of glutathione disulfide and oxidative stress monitoring using a biosensor

A highly sensitive in vivo biosensor for glutathione disulfide (GSSG) is developed using covalently immobilized-glutathione reductase (GR) and -β-nicotinamide adenine dinucleotide phosphate (NADPH) on gold nanoparticles deposited on poly[2,2′:5′,2″-terthiophene-3′-(p-benzoic acid)] (polyTTBA). The fabricated biosensor was characterized with SEM, TEM, XPS, and QCM. Analytical parameters affecting the biosensor performance were optimized in terms of applied potential, NADPH:GR ratio, temperature, and pH. A linear calibration plot is obtained using chronoamperometry in the dynamic range between 0.1 μM and 2.5 mM of GSSG, with a detection limit of 12.5 ± 0.5 nM. The developed biosensor is applied to detect GSSG in a real plasma sample. A microbiosensor was applied to detect the in vivo GSSG concentration to monitor the oxidative stress caused by diquat and t-butyl hydroperoxide. The results obtained are reliable, implying a promising approach for a GSSG biosensor in clinical diagnostics and oxidative stress monitoring.     

Is there a circadian rhythm of interleukin 15 in humans?

Nine healthy young men were studied under strict conditions for 48 h. The subjects were selected after a clinical examination and exploration of their rest-activity rhythm by actometry. The circadian rhythms of cortisol (peak at 8 AM) and melatonin (peak at 4 AM) were confirmed. The interleukin 15 (IL-15) was detected in the plasma samples with an Elisa kit (R&D System), but no reproducible variation could be observed during day 1 and day 2. In conclusion, in the conditions of our study, no rhythm was observed for IL-15. Our population will be completed with the inclusion of 6 additional subjects. These results will be specified.     

Is high-frequency neuromuscular electrical stimulation a suitable tool for muscle performance improvement in both healthy humans and athletes?

We aimed at providing an overview of the currently acknowledged benefits and limitations of neuromuscular electrical stimulation (NMES) training programs in both healthy individuals and in recreational and competitive athletes regarding muscle performance. Typical NMES resistance exercises are performed under isometric conditions and involve the application of electrical stimuli delivered as intermittent high frequencies trains (>40–50 Hz) through surface electrodes. NMES has been acknowledged as an efficient modality leading to significant improvements in isometric maximal voluntary strength. However, the resulting changes in dynamic strength, motor performance skills and explosive movements (i.e., jump performance, sprint ability) are still ambiguous and could only be obtained when NMES is combined with voluntary dynamic exercise such as plyometrics. Additionally, the effects of NMES on muscle fatigability are still poorly understood and required further investigations. While NMES effectiveness could be partially related to several external adjustable factors such as training intensity, current characteristics (e.g., intensity, pulse duration…) or the design of training protocols (number of contractions per session, number of sessions per week…), anatomical specificities (e.g., morphological organization of the axonal branches within the muscle) appear as the main factor accounting for the differences in NMES response. Overall, NMES cannot be considered as a surrogate training method, but rather as an adjunct to voluntary resistance training. The combination of these two training modalities should optimally improve muscle function.     

Metabolic implications of resistive force selection for oxidative stress and markers of muscle damage during 30 s of high-intensity exercise

The purpose of this study was to compare power outputs, and blood concentrations of lipid hydroperoxides (LH), malondialdehyde (MDA), creatine kinase (CK), myoglobin (Mb) and lactate ([La^–]_B) following 30 s of maximal cycle ergometry when resistive forces were derived from total-body mass (TBM) or fat-free mass (FFM). Alpha-tocopherol (AT), retinol (R) and uric acid (UA) concentrations were also measured to qualify the activity of antioxidants. Cardiac troponin levels were determined to exclude myocardial damage and to verify that any CK was predominantly derived from skeletal muscle. Differences (P<0.05) in peak power output, pedal velocity and resistive forces were observed when the TBM and FFM protocols were compared [953 (114) W vs 1,020 (134) W; 134 (8) rpm vs 141 (7) rpm; 6 (1) kg vs 5 (1) kg respectively). LH and MDA concentrations increased immediately post-exercise during the TBM protocol only (P<0.05) and were greater when compared to FFM (P<0.05). LH and MDA values decreased 24 h post-exercise. Increases in CK concentrations were recorded immediately post-exercise for both the TBM and FFM protocols with greater concentrations recorded for TBM (P<0.05). Decreases were observed 24 h post-exercise. Mb concentrations were greater immediately post-exercise for the TBM protocol and were greater than those recorded for FFM (P<0.05). Values decreased 24 h later (P<0.05). AT and UA concentrations decreased immediately post-exercise for both protocols (P<0.05) and increased 24 h later (P<0.05). There were no changes observed in R concentrations at any of the blood sampling stages. [La^–]_B increased (P<0.05) immediately post-exercise for both protocols, and decreased 24 h later (P<0.05). The results of the study suggest that greater power outputs are obtainable with significantly less oxidative stress and muscle disruption when resistive forces reflect FFM mass as opposed to TBM.     

Dimorphic effect of 17β-oestradiol on pathology and oxidative stress in experimental malaria

Malaria is the parasitic disease with the highest mortality worldwide; males exhibit higher mortality and more severe symptomatology than females, suggesting the participation of sexual hormones in protection and pathology. We have documented that gonadectomy modifies oxidative stress in Plasmodium berghei ANKA-infected mice in a dimorphic manner. However, gonadectomy decreases all sexual steroids levels, making it difficult to determine the contribution of each hormone to the results. This study aimed to explore the participation of 17β-oestradiol (E2) in oxidative stress in the blood, spleen, liver and brain of P. berghei-infected female and male mice. E2 was administered to intact or gonadectomized (GX) male and female mice to assess their effects on parasitaemia, body weight loss and hypothermia. We also measured the effect of E2 on the specific activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) and on malondialdehyde (MDA) levels in the blood, spleen, liver and brain of CBA/Ca male and female mice infected with P. berghei ANKA.We detected the effects of E2 and sexual dimorphism on all tissues and variables analysed. Administration of E2 increased parasitaemia in intact mice. However, reconstitution of GX female mice with E2 decreased parasitaemia. E2 decreased body weight and differentially modulated oxidative stress depending on the sex, infection and tissue analysed. Low antioxidant activity was detected in the brain, suggesting additional protective antioxidant mechanisms in the brain independent of antioxidant enzymes. Our results explained, at least in part, the sexual dimorphism in this experimental model of malaria.