Overexpression of copper zinc superoxide dismutase impairs human trophoblast cell fusion and differentiation.: SOD-1 and Human Trophoblast Differentiation

The syncytiotrophoblast is the major component of the human placenta, involved in feto-maternal exchanges and secretion of pregnancy-specific hormones. Multinucleated syncytiotrophoblast arises from fusion of mononuclear cytotrophoblast cells. In trisomy 21-affected placentas, we recently have shown that there is a defect in syncytiotrophoblast formation and a decrease in the production of pregnancy-specific hormones. Due to the role of oxygen free radicals in trophoblast cell differentiation, we investigated the role of the key antioxidant enzyme, copper/zinc superoxide dismutase, encoded by chromosome 21 in in vitro trophoblast differentiation. We first observed that overexpression of superoxide dismutase in normal cytotrophoblasts impaired syncytiotrophoblast formation. This was associated with a significant decrease in mRNA transcript levels and secretion of hCG and other hormonal markers of syncytiotrophoblast. We confirmed abnormal cell fusion by overexpression of green fluorescence protein-tagged superoxide dismutase in cytotrophoblasts. In addition, a significant decrease in syncytin transcript levels was observed in superoxide dismutase-transfected cells. We then examined superoxide dismutase expression and activity in isolated trophoblast cells from trisomy 21-affected placentas. Superoxide dismutase mRNA expression (P < 0.05), protein levels (P < 0.01), and activity (P < 0.05) were significantly higher in trophoblast cells isolated from trisomy 21-affected placentas than in those from normal placentas. These results suggest that superoxide dismutase overexpression may directly impair trophoblast cell differentiation and fusion, and superoxide dismutase overexpression in Down's syndrome may be responsible at least in part for the failure of syncytiotrophoblast formation observed in trisomy 21-affected placentas

Peroxiredoxin 6 Fails to Limit Phospholipid Peroxidation in Lung from Cftr-Knockout Mice Subjected to Oxidative Challenge

Oxidative stress plays a prominent role in the pathophysiology of cystic fibrosis (CF). Despite the presence of oxidative stress markers and a decreased antioxidant capacity in CF airway lining fluid, few studies have focused on the oxidant/antioxidant balance in CF cells. The aim of the current study was to investigate the cellular levels of reactive oxygen species (ROS), oxidative damage and enzymatic antioxidant defenses in the lung of Cftr-knockout mice in basal conditions and as a response to oxidative insult

Targeting mitochondrial function in macrophages: A novel treatment strategy for atherosclerotic cardiovascular disease?

International audienceAtherosclerotic cardiovascular disease is a major cause of morbidity and mortality due to chronic arterial injury caused by hyperlipidemia, hypertension, inflammation and oxidative stress. Recent studies have shown that the progression of this disease is associated with mitochondrial dysfunction and with the accumulation of mitochondrial alterations within macrophages of atherosclerotic plaques. These alterations contribute to processes of inflammation and oxidative stress. Among the many players involved, macrophages play a pivotal role in atherogenesis as they can exert both beneficial and deleterious effects due to their anti-and pro-inflammatory properties. Their atheroprotective functions, such as cholesterol efflux and efferocytosis, as well as the maintenance of their polarization towards an anti-inflammatory state, are particularly dependent on mitochondrial metabolism. Moreover, in vitro studies have demonstrated deleterious effects of oxidized LDL on macrophage mitochondrial function, resulting in a switch to a pro-inflammatory state and to a potential loss of atheroprotective capacity. Therefore, preservation of mitochondrial function is now considered a legitimate therapeutic strategy. This review focuses on the potential therapeutic strategies that could improve the mitochondrial function of macrophages, enabling them to maintain their atheroprotective capacity. These emerging therapies could play a valuable role in counteracting the progression of atherosclerotic lesions and possibly inducing their regression

Role of Sex Hormones on Brain Mitochondrial Function, with Special Reference to Aging and Neurodegenerative Diseases

The mitochondria have a fundamental role in both cellular energy supply and oxidative stress regulation and are target of the effects of sex steroids, particularly the neuroprotective ones. Aging is associated with a decline in the levels of different steroid hormones, and this decrease may underline some neural dysfunctions. Besides, modifications in mitochondrial functions associated with aging processes are also well documented. In this review, we will discuss studies that describe the modifications of brain mitochondrial function and of steroid levels associated with physiological aging and with neurodegenerative diseases. A special emphasis will be placed on describing and discussing our recent findings concerning the concomitant study of mitochondrial function (oxidative phosphorylation, oxidative stress) and brain steroid levels in both young (3-month-old) and aged (20-month-old) male and female mice

Analysis of the resistivity loss of aged PVC cables and effects on their dielectric strength

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Antioxidant Enzymes in Psoriatic Fibroblasts and Erythrocytes

Antioxidant enzyme activities in fibroblasts and erythrocytes prepared from normal and psoriatic patients were measured and compared. The most significant differences were noted in superoxide dismutase (SOD) activities. A dramatic (5.2-fold) increase in Mn-SOD activity along with a lesser (1.8-fold) increase in CuZn-SOD activity was observed in fibroblasts from lesional and nonlesional psoriatic skin. the increase of Mn-SOD activity was correlated with an increase of both protein and mRNA. A slight (1.2-fold) increase in CuZn-SOD activity was also found in psoriatic as compared to normal red blood cells, while Mn-SOD activity was not present in these cells. In contrast, both glutathione peroxidase and catalase activities were only slightly (1.3-fold) increased in psoriatic fibroblasts, with no appreciable change noted in psoriatic erythrocytes. Likewise, glutathione levels were observed to be similar in normal and psoriatic cells. The increases in SOD activities did not appear to correlate with the severity of the disease as expressed by the Psoriatic Area Severity Index score or with plasma inflammatory markers. These results demonstrate that antioxidant enzyme activities, particularly Mn-SOD in fibroblasts and CuZn-SOD in erythrocytes, are significantly elevated in cells from psoriatic patients

Cholesterol accumulation induced by acetylated LDL exposure modifies the enzymatic activities of the TCA cycle without impairing the respiratory chain functionality in macrophages

International audienceThe unregulated uptake of modified low-density lipoproteins (LDL) by macrophages leads to foam cell formation, promoting atherosclerotic plaque progression. The cholesterol efflux capacity of macrophages by the ATP-Binding Cassette transporters depends on the ATP mitochondrial production. Therefore, the mitochondrial function maintenance is crucial in limiting foam cell formation. Thus, we aimed to investigate the mechanisms involved in the mitochondrial dysfunction that may occur in cholesterol-laden macrophages. We incubated THP-1 macrophages with acetylated LDL (acLDL) to obtain cholesterol-laden cells or with mildly oxidized LDL (oxLDL) to generate cholesterol- and oxidized lipids-laden cells. Cellular cholesterol content was measured in each condition. Mitochondrial function was evaluated by measurement of several markers of energetic metabolism, oxidative phosphorylation, oxidative stress, mitochondrial biogenesis and dynamics. OxLDL-exposed macrophages exhibited a significantly reduced mitochondrial respiration and complexes I and III activities, associated to an oxidative stress state and a reduced mitochondrial DNA copy number. Meanwhile, acLDL-exposed macrophages featured an efficient oxidative phosphorylation despite the decreased activities of aconitase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. Our study revealed that mitochondrial function was differently impacted according to the nature of modified LDL. Exposure to cholesterol and oxidized lipids carried by oxLDL leads to a mitochondrial dysfunction in macrophages, affecting the mitochondrial respiratory chain functional capacity, whereas the cellular cholesterol enrichment induced by acLDL exposure results in a tricarboxylic acid cycle shunt while maintaining mitochondrial energetic production, reflecting a metabolic adaptation to cholesterol intake. These new mechanistic insights are of direct relevance to the understanding of the mitochondrial dysfunction in foam cells