Biochimica et biophysica acta
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Biochim. Biophys. Acta · Feb 2014
Redox-optimized ROS balance and the relationship between mitochondrial respiration and ROS.
The Redox-Optimized ROS Balance [R-ORB] hypothesis postulates that the redox environment [RE] is the main intermediary between mitochondrial respiration and reactive oxygen species [ROS]. According to R-ORB, ROS emission levels will attain a minimum vs. RE when respiratory rate (VO2) reaches a maximum following ADP stimulation, a tenet that we test herein in isolated heart mitochondria under forward electron transport [FET]. ⋯ We conclude that under non-stressful conditions mitochondrial ROS efflux decreases when the RE becomes less reduced within a range in which VO2 is maximal. These results agree with the R-ORB postulate that mitochondria minimize ROS emission as they maximize VO2 and ATP synthesis. This relationship is altered quantitatively, but not qualitatively, by oxidative stress although stressed mitochondria exhibit diminished energetic performance and increased ROS release.
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Biochim. Biophys. Acta · Jan 2014
Randomized Controlled TrialResveratrol enhances TNF-α production in human monocytes upon bacterial stimulation.
Resveratrol is a key component of red wine that has been reported to have anti-carcinogenic and anti-aging properties. Additional studies conducted in vitro and in animal models suggested anti-inflammatory properties. However, data from primary human immune cells and in vivo studies are limited. ⋯ By administering resveratrol to healthy humans and utilizing primary immune cells we were able to detect TNF-α enhancing properties of the agent. In parallel, we found enhanced alternative NF-κB activation. We report on a novel pro-inflammatory property of resveratrol which has to be considered in concepts of its biologic activity.
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Biochim. Biophys. Acta · Jan 2014
Prophylactic systemic P2X7 receptor blockade prevents experimental colitis.
The P2X7 receptor (P2X7-R) is a non-selective adenosine triphosphate-gated cation channel present in epithelial and immune cells, and involved in inflammatory response. Extracellular nucleotides released in conditions of cell stress or inflammation may function as a danger signal alerting the immune system from inflammation. We investigated the therapeutic action of P2X7-R blockade in a model of inflammatory bowel disease. ⋯ Prophylactic systemic P2X7-R blockade is effective in the prevention of experimental colitis, probably due to a systemic anti-inflammatory action, interfering with a stress-inflammation amplification loop mediated by P2X7-R.
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Biochim. Biophys. Acta · Jan 2014
Anti-inflammatory action of lipid nanocarrier-delivered myriocin: therapeutic potential in cystic fibrosis.
Sphingolipids take part in immune response and can initiate and/or sustain inflammation. Various inflammatory diseases have been associated with increased ceramide content, and pharmacological reduction of ceramide diminishes inflammation damage in vivo. Inflammation and susceptibility to microbial infection are two elements in a vicious circle. Recently, sphingolipid metabolism inhibitors were used to reduce infection. Cystic fibrosis (CF) is characterized by a hyper-inflammation and an excessive innate immune response, which fails to evolve into adaptive immunity and to eradicate infection. Chronic infections result in lung damage and patient morbidity. Notably, ceramide content in mucosa airways is higher in CF mouse models and in patients than in control mice or healthy subjects. ⋯ Myriocin stands as a powerful immunomodulatory agent for inflammatory and infectious diseases.
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Biochim. Biophys. Acta · Jan 2014
The roles of C-terminal helices of human apolipoprotein A-I in formation of high-density lipoprotein particles.
Apolipoprotein A-I (apoA-I) accepts cholesterol and phospholipids from ATP-binding cassette transporter A1 (ABCA1)-expressing cells to form high-density lipoprotein (HDL). Human apoA-I has two tertiary structural domains and the C-terminal domain (approximately amino acids 190-243) plays a key role in lipid binding. Although the high lipid affinity region of the C-terminal domain of apoA-I (residues 223-243) is essential for the HDL formation, the function of low lipid affinity region (residues 191-220) remains unclear. ⋯ In addition, the ability to form HDL particles in vitro and induce cholesterol efflux from ABCA1-expressing cells of Δ191-220 apoA-I was also intermediate between wild-type and Δ223-243 apoA-I. These results suggest that despite possessing low lipid affinity, residues 191-220 play a role in enhancing the ability of apoA-I to bind to and solubilize lipids by forming α-helix upon lipid interaction. Our results demonstrate that the combination of low lipid affinity region and high lipid affinity region of apoA-I is required for efficient ABCA1-dependent HDL formation.