비만아 부모의 돌봄 경험: q 방법론

NAD(+) Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus.

The balance between oxidation and antioxidation is believed to be critical in maintaining healthy biological systems. Under physiological conditions, the human antioxidative defense system including e.g., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH) and others, allows the elimination of excess reactive oxygen species (ROS) including, among others superoxide anions (O2(·-)), hydroxyl radicals (OH·), alkoxyl radicals (RO·) and peroxyradicals (ROO·). However, our endogenous antioxidant defense systems are incomplete without exogenous originating reducing compounds such as vitamin C, vitamin E, carotenoids and polyphenols, playing an essential role in many antioxidant mechanisms in living organisms. Therefore, there is continuous demand for exogenous antioxidants in order to prevent oxidative stress, representing a disequilibrium redox state in favor of oxidation. However, high doses of isolated compounds may be toxic, owing to prooxidative effects at high concentrations or their potential to react with beneficial concentrations of ROS normally present at physiological conditions that are required for optimal cellular functioning. This review aims to examine the double-edged effects of dietary originating antioxidants with a focus on the most abundant compounds, especially polyphenols, vitamin C, vitamin E and carotenoids. Different approaches to enrich our body with exogenous antioxidants such as via synthetic antioxidants, diets rich in fruits and vegetables and taking supplements will be reviewed and experimental and epidemiological evidences discussed, highlighting that antioxidants at physiological doses are generally safe, exhibiting interesting health beneficial effects.

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Exogenous antioxidants--Double-edged swords in cellular redox state: Health beneficial effects at physiologic doses versus deleterious effects at high doses.

The literature on atmospheric particulate maffer (PM), or atmospheric aerosol, has increased enormously over the last 2 decades and amounts now to some 1500—2000 papers per year in the refereed literature. This is in part due to the enormous advances in measurement technologies, which have allowed for an increasingly accurate understanding of the chemical composition and of the physical properties of atmospheric particles and of their processes in the atmosphere. The growing scientific interest in atmospheric aerosol particles is due to their high importance for environmental policy. In fact, particulate maffer constitutes one of the most challenging problems both for air quality and for climate change policies. In this context, this paper reviews the most recent results within the atmospheric aerosol sciences and thepoticy needs, which have driven much ofthe increase in monitoring and mechanistic research over the last 2 decades. The synthesis reveals many new processes and developments in the science underpinning climate—aerosol interactions and effects of PM on human health and the environment. However, while airborne particulate matter is responsible for globally important influences on premature human mortality, we stijl do not know the relative importance of the different chemical components of PM for these effects. Likewise, the magnitude of the overall effects of PM on climate remains highly uncertain. Despite the uncertainty there are many things that could be done to mitigate local and global problems of atmospheric PM. Recent analyses have shown that reducing black carbon (BC) emissions, using known control measures, would reduce global wanning and delay the time when anthropogenic effects on global temperature would exceed 2°C. Likewise, cost-effective control measures on ammonia, an important agricultural precursor gas for secondary inorganic aerosols (SlA), would reduce regional eutrophication and PM concentrations in large areas of Europe, China and the USA. Thus, there is much that could be done to reduce the effects of atmospheric PM on the climate and the health of the environment and the human population. A prioritized list of actions to mitigate the full range of effects ofPM is currently undeliverable due to shortcomings in the knowledge of aerosol science; among the shortcomings, the roles of PM in global climate and the relative roles of different PM precursor sources and their response to climate and land use change over the remaining decades of this century are prominent. In any case, the evidence from this paper strongly advocates for an integrated approach to air quality and climate policies.

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Particulate matter, air quality and climate: Lessons learned and future needs

MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

Air pollution is associated with increased cardiovascular and pulmonary morbidity and mortality. The mechanisms of air pollution-induced health effects involve oxidative stress and inflammation. As a matter of fact, particulate matter (PM), especially fine (PM2.5, PM < 2.5 μm) and ultrafine (PM0.1, PM < 0.1 μm) particles, ozone, nitrogen oxides, and transition metals, are potent oxidants or able to generate reactive oxygen species (ROS). Oxidative stress can trigger redox-sensitive pathways that lead to different biological processes such as inflammation and cell death. However, it does appear that the susceptibility of target organ to oxidative injury also depends upon its ability to upregulate protective scavenging systems. As vehicular traffic is known to importantly contribute to PM exposure, its intensity and quality must be strongly relevant determinants of the qualitative characteristics of PM spread in the atmosphere. Change in the composition of this PM is likely to modify its health impact.

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Oxidative Stress and Air Pollution Exposure

Type 2 diabetes (T2DM) and its complications constitute a major worldwide public health problem, with high rates of morbidity and mortality. Biomarkers for predicting the occurrence and development of the disease may therefore offer benefits in terms of early diagnosis and intervention. This review provides an overview of human studies on circulating biomarkers of oxidative stress and antioxidant defence systems and discusses their usefulness from a clinical perspective. Most case-control studies documented an increase in biomarkers of oxidative lipid, protein, and nucleic acid damage in patients with prediabetes and in those with a diagnosis of T2DM compared to controls, and similar findings were reported in T2DM with micro- and macrovascular complications compared to those without. The inconsistence of the results regarding antioxidant defence systems renders difficulty to draw a general conclusion. The clinical relevance of biomarkers of oxidative lipid and protein damage for T2DM progression is uncertain, but prospective studies suggest that markers of oxidative nucleic acid damage such as 8-hydroxy-2'-deoxyguanosine and 8-hydroxyguanosine are promising for predicting macrovascular complications of T2DM. Emerging evidence also points out the relationship between serum PON1 and serum HO1 in T2DM and its complications. Overall, enhanced oxidative damage represents an underlying mechanism of glucose toxicity in T2DM and its related micro- and macrovascular complications suggesting that it may be considered as a potential additional target for pharmacotherapy. Therefore, further studies are needed to understand whether targeting oxidative stress may yield clinical benefits. In this view, the measurement of oxidative stress biomarkers in clinical trials deserves to be considered as an additional tool to currently used parameters to facilitate a more individualized treatment of T2DM in terms of drug choice and patient selection.

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Circulating Oxidative Stress Biomarkers in Clinical Studies on Type 2 Diabetes and Its Complications

During the last several years, evidence that various enzymes hydrolyze NAD into bioactive products prompted scientists to revisit or design strategies able to increase intracellular availability of the dinucleotide. However, plasma membrane permeability to NAD and the mitochondrial origin of the dinucleotide still wait to be clearly defined. Here, we report that intracellular NAD contents increased upon exposure of cell lines or primary cultures to exogenous NAD (eNAD). NAD precursors could not reproduce the effects of eNAD, and they were not found in the incubating medium containing eNAD, thereby suggesting direct cellular eNAD uptake. We found that in mitochondria of cells exposed to eNAD, NAD and NADH as well as oxygen consumption and ATP production were increased. Conversely, DNA repair, a well known NAD-dependent process, was unaltered upon eNAD exposure. We also report that eNAD conferred significant cytoprotection from apoptosis triggered by staurosporine, C2-ceramide, or N-methyl-N'-nitro-N-nitrosoguanidine. In particular, eNAD reduced staurosporine-induced loss of mitochondrial membrane potential and ensuing caspase activation. Of importance, pharmacological inhibition or silencing of the NAD-dependent enzyme SIRT1 abrogated the ability of eNAD to provide protection from staurosporine, having no effect on eNAD-dependent protection from C2-ceramide or N-methyl-N'-nitro-N-nitrosoguanidine. Taken together, our findings, on the one hand, strengthen the hypothesis that eNAD crosses the plasma membrane intact and, on the other hand, provide evidence that increased NAD contents significantly affects mitochondrial bioenergetics and sensitivity to apoptosis.

https://molpharm.aspetjournals.org/content/molpharm/early/2011/09/14/mol.111.073916.full.pdf

Pharmacological Effects of Exogenous NAD on Mitochondrial Bioenergetics, DNA Repair and Apoptosis

Diabetes mellitus is a complex metabolic disorder characterized by a disturbance in glucose metabolism. Recent evidence suggests that increased oxidative damage as well as reduction in antioxidant capacity could be related to the complications in patients with type 2 diabetes. The aim of this study was to measure plasma antioxidant status in type 2 diabetic patients with good and poor glycaemic control and its relationship with oxidative DNA damage. Thirty-nine type 2 diabetic patients and eighteen healthy subjects were recruited for this study. We found that diabetic patients had slightly, but not significantly lower antioxidant capacity, measured with the "ferric reducing ability of plasma" (FRAP) assay, than healthy subjects. On the contrary, oxidative DNA damage (measured by the Comet assay) in leukocytes obtained from diabetic patients was significantly higher compared to healthy subjects. Taking into account glucose control, we found that the FRAP level was significantly (p<0.05) lower in diabetic subjects with poor glycaemic control than healthy subjects, while patients with good glycaemic control had FRAP values similar to controls. We also observed an unexpected positive correlation between FRAP values and oxidative DNA damage in diabetic patients; moreover, a positive correlation was found between FRAP and glucose level or HbA(1c) in patients with poor glycaemic control. In conclusion, our results confirm that patients with type 2 diabetes have a higher oxidative DNA damage than healthy subjects and that plasma antioxidant capacity is significantly lower only in patients with poor glycaemic control, moreover, in these patients FRAP values are positively correlated with glycaemic levels and HbA(1c). These observations indicate that a compensatory increase of the antioxidant status is induced as a response to free radical overproduction in type 2 diabetes. Therefore, the addition of antioxidant supplements to the current pharmacological treatment could have potentially beneficial effects in diabetic patients with poor glycaemic control.

Oxidative DNA damage and plasma antioxidant capacity in type 2 diabetic patients with good and poor glycaemic control.

Cancer-secreted exosomes influence tumor microenvironment and support cancer growth and metastasis. MiR-210 is frequently up-regulated in colorectal cancer tissues and correlates with metastatic disease. We investigated whether exosomes are actively released by HCT-8 colon cancer cells, the role of exosomal miR-210 in the cross-talk between primary cancer cells and neighboring metastatic cells and its contribution in regulating epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET). After 7 d of culture, a subpopulation of viable HCT-8 cells detached the monolayer and started to grow in suspension, suggesting anoikis resistance and a metastatic potential. The expression of key proteins of EMT revealed that these cells were E-cadherin negative and vimentin positive further confirming their metastatic phenotype and the acquisition of anoikis resistance. Metastatic cells, in the presence of adherently growing HCT-8, continued to grow in suspension whereas only if seeded in cell-free wells, were able to adhere again and to form E-cadherin positive and vimentin negative new colonies, suggesting the occurrence of MET. The chemosensitivity to 5 fluorouracil and to FOLFOX-like treatment of metastatic cells was significantly diminished compared to adherent HCT-8 cells. Of note, adherent new colonies undergoing MET, were insensitive to both chemotherapeutic strategies. Electron microscopy analysis demonstrated that adherently growing HCT-8, actually secreted exosomes and that exosomes in turn were taken up by metastatic cells. When exosomes secreted by adherently growing HCT-8 were administered to metastatic cells, MET was significantly inhibited. miR-210 was significantly upregulated in exosomes compared to its intracellular levels in adherently growing HCT-8 cells and correlated to anoikis resistance and EMT markers. Exosomes containing miR-210 might be considered as EMT promoting signals that preserve the local cancer-growth permissive milieu and also guide metastatic cells to free, new sites of dissemination.

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Elisabetta Bigagli

Papers

Oxidative Stress and Air Pollution Exposure

Circulating Oxidative Stress Biomarkers in Clinical Studies on Type 2 Diabetes and Its Complications

Pharmacological Effects of Exogenous NAD on Mitochondrial Bioenergetics, DNA Repair and Apoptosis

Oxidative DNA damage and plasma antioxidant capacity in type 2 diabetic patients with good and poor glycaemic control.

Exosomes secreted from human colon cancer cells influence the adhesion of neighboring metastatic cells: Role of microRNA-210