Background:Mn 2ϩ levels are lower in blood of diabetic and atherosclerosis patients. Results: Mn 2ϩ supplementation reduces monocyte adhesion in endothelial cells by down-regulating ROS, ICAM-1 expression, and MCP-1 secretion, and lowers blood levels of ICAM-1 and cholesterol in ZDF rats. Conclusion:Mn 2ϩ supplementation is beneficial in lowering markers of endothelial dysfunction. Significance: Mn 2ϩ supplementation can potentially prevent or delay progression of atherosclerosis.Endothelial dysfunction is a hallmark of increased vascular inflammation, dyslipidemia, and the development of atherosclerosis in diabetes. Previous studies have reported lower levels of Mn 2؉ in the plasma and lymphocytes of diabetic patients and in the heart and aortic tissue of patients with atherosclerosis. This study examines the hypothesis that Mn 2؉ supplementation can reduce the markers/risk factors of endothelial dysfunction in type 2 diabetes. Human umbilical vein endothelial cells (HUVECs) were cultured with or without Mn 2؉ supplementation and then exposed to high glucose (HG, 25 mM) to mimic diabetic conditions. Mn 2؉ supplementation caused a reduction in monocyte adhesion to HUVECs treated with HG or MCP-1. Mn 2؉ also inhibited ROS levels, MCP-1 secretion, and ICAM-1 up-regulation in HUVECs treated with HG. Silencing studies using siRNA against MnSOD showed that similar results were observed in MnSOD knockdown HUVECs following Mn 2؉ supplementation, suggesting that the effect of manganese on monocyte adhesion to endothelial cells is mediated by ROS and ICAM-1, but not MnSOD. To validate the relevance of our findings in vivo, Zucker diabetic fatty rats were gavaged daily with water (placebo) or MnCl 2 (16 mg/kg of body weight) for 7 weeks. When compared with placebo, Mn 2؉ -supplemented rats showed lower blood levels of ICAM-1 (17%, p < 0.04), cholesterol (25%, p < 0.05), and MCP-1 (28%, p ؍ 0.25). These in vitro and in vivo studies demonstrate that Mn 2؉ supplementation can down-regulate ICAM-1 expression and ROS independently of MnSOD, leading to a decrease in monocyte adhesion to endothelial cells, and therefore can lower the risk of endothelial dysfunction in diabetes.Manganese is an essential micronutrient that serves as a cofactor for many enzyme systems. Metalloenzymes, or manganese-containing enzymes, such as arginase, pyruvate carboxylase, and manganese superoxide dismutase (MnSOD), 2 require Mn 2ϩ to function. MnSOD is the major mitochondrial antioxidant and is responsible for protecting the cell from reactive oxygen species (ROS) by scavenging mitochondrial superoxide (1). MnSOD acts by catalyzing the conversion of superoxide radicals (such as O 2 ) to hydrogen peroxide, which is further metabolized to water by other antioxidant enzymes such as catalase and glutathione peroxidase (2). At low concentrations, Mn 2ϩ ions have been shown to have antioxidant properties with the ability to scavenge superoxide and hydroxyl radicals (3). Several studies have reported that changes in dietary Mn 2ϩ induced changes in MnS...
Stationary-phase Saccharomyces cerevisiae cells transferred from spent rich media into water live for weeks, whereas the same cells die within hours if transferred into water with 2% glucose in a process called sugar-induced cell death (SICD). Our hypothesis is that SICD is due to a dysregulated Crabtree effect, which is the phenomenon whereby glucose transiently inhibits respiration and ATP synthesis. We found that stationary-phase cells in glucose/water consume 21 times more O 2 per cell than exponential-phase cells in rich media, and such excessive O 2 consumption causes reactive oxygen species to accumulate. We also found that inorganic phosphate and succinate protect against SICD but by different mechanisms. Phosphate protects by triggering the synthesis of Fru-1,6-P 2 , which inhibits respiration in isolated mitochondria. Succinate protects in wild-type cells but fails to protect in dic1⌬ cells. DIC1 codes for a mitochondrial inner membrane protein that exchanges cytosolic succinate for matrix phosphate. We propose that succinate depletes matrix phosphate, which in turn inhibits respiration and ATP synthesis. In sum, restoring the Crabtree effect, whether with phosphate or succinate, protects cells from SICD.Saccharomyces cerevisiae cells undergo glucose-induced inhibition of respiration and oxidative phosphorylation and a parallel up-regulation of both glycolysis and glucose uptake by a short-term mechanism called the "Crabtree effect" (1-5). The Crabtree effect is a reversible process, and the precise mechanism of this phenomenon is controversial (6 -8). In addition to the down-regulation of genes involved in respiration and oxidative phosphorylation by glucose (9, 10), the Crabtree effect may involve competition between mitochondrial respiratory enzymes and glycolytic enzymes for ADP and inorganic phosphate (11, 12), changes in the permeability of the outer mitochondrial membrane (8), and the accumulation of certain metabolic intermediates, especially Fru-1,6-P 2 (6).The possibility that Fru-1,6-P 2 mediates the Crabtree effect was shown in a recent study that used mitochondria isolated from Crabtree-positive and Crabtree-negative yeast (6).Notably, Fru-1,6-P 2 decreased the rate of O 2 consumption in mitochondria isolated from the Crabtree-positive yeast (S. cerevisiae), but not that in mitochondria isolated from the Crabtree-negative yeast (Candida utilis). Such a result indicates that Fru-1,6-P 2 mediates the Crabtree effect.Although glucose triggers the Crabtree effect when yeast cells are cultured in rich media, glucose in water is very toxic to cells, especially stationary-phase (G 0 ) cells. When stationaryphase cells are shifted into 2% glucose or fructose in water, the cells begin to bud but then rapidly lose viability within a few hours (13,14). The cells undergo an apoptotic death triggered by reactive oxygen species (ROS) 2 accumulation (15). ROS accumulation suggests that the respiratory pathway in mitochondria is turned on rather than repressed. The sugar-induced cell death (SICD) is indep...
A recombinant vaccine composed of a fusion protein formulated with aluminum hydroxide adjuvant is under development for protection against diseases caused by Streptococcus pyogenes. The safety and local reactogenicity of the vaccine was assessed by a comprehensive series of clinical, pathologic and immunologic tests in preclinical experiments. Outbred mice received three intramuscular injections of 1/5th of the human dose (0.1 ml) and rabbits received two injections of the full human dose. Control groups received adjuvant or protein antigen. The vaccine did not cause clinical evidence of systemic toxicity in mice or rabbits. There was a transient increase of peripheral blood neutrophils after the third vaccination of mice. In addition, the concentration of acute phase proteins serum amyloid A and haptoglobin was significantly increased 1 day after injection of the vaccine in mice. There was mild transient swelling and erythema of the injection site in both mice and rabbits. Treatment-related pathology was limited to inflammation at the injection site and accumulation of adjuvant-containing macrophages in the draining lymph nodes. In conclusion, the absence of clinical toxicity in two animal species suggest that the vaccine is safe for use in a phase I human clinical trial. Copyright © 2016 John Wiley & Sons, Ltd.
Blood and tissue levels of manganese (Mn) are lower in type 2 diabetic and atherosclerosis patients compared with healthy subjects. Adiponectin has anti-diabetic and anti-atherogenic properties. Impairment in Disulfide bond A-like protein (DsbA-L) is associated with low adiponectin levels and diabetes. This study investigates the hypothesis that the beneficial effects of Mn supplementation are mediated by adiponectin and DsbA-L. At 6 weeks of age, Male Zucker diabetic fatty rats (ZDF) were randomly divided into two groups: diabetic controls and Mn-supplemented diabetic rats. Each rat was supplemented with Mn (D+Mn, 16 mg/kg BW) or water (placebo, D+P) daily for 7 weeks by oral gavage. For cell culture studies, Human Umbilical Vein Endothelial Cells (HUVEC) or 3T3L1 adipocytes were pretreated with Mn (0-10 µM MnCl) for 24 h, followed by high glucose (HG, 25 mM) or normal glucose (5 mM) exposure for another 24 h. Mn supplementation resulted in higher adiponectin (p = 0.01), and lower ICAM-1 (p = 0.04) and lower creatinine (p = 0.04) blood levels compared to those in control ZDF rats. Mn-supplemented rats also caused reduced oxidative stress (ROS) and NADPH oxidase, and higher DsbA-L expression in the liver (p = 0.03) of ZDF rats compared to those in livers of control rats; however, Fe levels in liver were lower but not significant (p = 0.08). Similarly, treatment with high glucose (25 mM) caused a decrease in DsbA-L, which was prevented by Mn supplementation in HUVEC and adipocytes. Mechanistic studies with DsbA-L siRNA showed that the beneficial effects of Mn supplementation on ROS, NOX4, and ICAM-1 expression were abolished in DsbA-L knock-down HUVEC. These studies demonstrate that DsbA-L-linked adiponectin mediates the beneficial effects observed with Mn supplementation and provides evidence for a novel mechanism by which Mn supplementation can increase adiponectin and reduce the biomarkers of endothelial dysfunction in diabetes.
The Prestwick and NIH chemical libraries were screened for drugs that protect baker’s yeast from sugar-induced cell death (SICD). SICD is triggered when stationary-phase yeast cells are transferred from spent rich medium into water with 2% glucose and no other nutrients. The rapid, apoptotic cell death occurs because reactive oxygen species (ROS) accumulate. We found that triclabendazole, which is used to treat liver flukes in cattle and man, partially protects against SICD. Characterization of triclabendazole revealed that it also protects yeast cells from death induced by the Parkinson’s disease-related protein alpha-synuclein (α-syn), which is known to induce the accumulation of ROS.
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