4-hydroxy-2-nonenal and Hyperglycemia

Since the landmark discovery of α,β-unsaturated 4-hydroxyalkenals by Esterbauer and colleagues most studies have addressed the consequences of the tendency of these lipid peroxidation products to form covalent adducts with macromolecules and modify cellular functions. Many studies describe detrimental and cytotoxic effects of 4-hydroxy-2E-nonenal (4-HNE) in myriad tissues and organs and many pathologies. Other studies similarly assigned unfavorable effects to 4-hydroxy-2E-hexenal (4-HHE) and 4-hydroxy-2E,6Z-dodecadienal (4-HDDE). Nutrient overload (e.g., hyperglycemia, hyperlipidemia) modifies lipid metabolism in cells and promotes lipid peroxidation and the generation of α,β-unsaturated 4-hydroxyalkenals. Advances glycation- and lipoxidation end products (AGEs and ALEs) have been associated with the development of insulin resistance and pancreatic beta cell dysfunction and the etiology of type 2 diabetes and its peripheral complications. Less acknowledged are genuine signaling properties of 4-hydroxyalkenals in hormetic processes that provide defense against the consequences of nutrient overload. This review addresses recent findings on such lipohormetic mechanisms that are associated with lipid peroxidation in pancreatic beta cells. This article is part of a Special Issue entitled SI: LIPID OXIDATION PRODUCTS, edited by Giuseppe Poli.

Topics: Aldehydes; Animals; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Glycation End Products, Advanced; Hormesis; Humans; Hyperglycemia; Hyperlipidemias; Insulin Resistance; Insulin-Secreting Cells; Lipid Peroxidation; Oxidative Stress; Phospholipases A2

Hyperglycemia leads to lipid peroxidation, producing 4-hydroxynonenal (HNE) adducts which correlate with the production of amyloid-beta (Aβ), one of the hallmarks of Alzheimer's disease (AD). This study is to investigate the interactions of Aβ, HNE adducts and responding autoantibodies during the pathogenesis from hyperglycemia to AD.. Increased fasting glucose and decreased high-density-lipoprotein cholesterol in AD groups indicated abnormal metabolism in the pathogenesis progression from hyperglycemia to AD. Indeed, serum Aβ, HNE adducts and most of the autoantibodies recognizing either native or HNE-modified Aβ were increased in the diseased groups. However, HNE adducts had better diagnostic performances than Aβ for both hyperglycemia and AD. Additionally, HNE-Aβ peptide levels were increased, and the responding autoantibodies (most notably IgM) were decreased in hyperglycemic AD group compared to the hyperglycemia only group, suggesting an immunity disturbance in the pathogenesis progression from hyperglycemia to AD.. Hyperglycemia increases the level of HNE adducts which may be neutralized by responding autoantibodies. Depletion of these autoantibodies promotes AD-like pathogenesis. Thus, levels of a patient's HNE adducts and associated responding autoantibodies are potential biomarkers for AD with diabetes.

Topics: Aged; Aged, 80 and over; Aldehydes; Alzheimer Disease; Amino Acid Sequence; Amyloid beta-Peptides; Antibodies, Neutralizing; Autoantibodies; Biomarkers; Blood Proteins; Case-Control Studies; Female; Humans; Hyperglycemia; Male; Peptide Fragments

Metabolic syndrome (MetS) is a predictor of cardiovascular diseases, commonly associated with oxidative stress and inflammation. However, the pathogenic mechanisms are not yet fully elucidated. The aim of the study is to evaluate the oxidative status and inflammation in the heart of obese Zucker rats (OZRs) and lean Zucker rats (LZRs) at different ages. Morphological and morphometric analyses were performed in the heart. To study the oxidative status, the malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), protein oxidation, and antioxidant enzymes were measured in plasma and heart. To elucidate the inflammatory markers involved, immunohistochemistry and Western blot were performed for cellular adhesion molecules and proinflammatory cytokines. OZRs were characterized by hypertension, hyperlipidemia, hyperglycemia, and insulin resistance. The obesity increased MDA and decreased the activities of superoxide dismutase (SOD) in plasma as well as in the heart, associated with cardiomyocytes hypertrophy. OxyBlot in plasma and in heart showed an increase of oxidativestate proteins in OZRs. Vascular cell adhesion molecule-1, interleukin-6, and tumor necrosis factor-α expressions in OZRs were higher than those of LZRs. However, these processes did not induce apoptosis or necrosis of cardiomyocytes. Thus, MetS induces the lipid peroxidation and decreased antioxidant defense that leads to heart tissue changes and coronary inflammation.

Topics: Aldehydes; Animals; Antioxidants; Cardiovascular System; Cytokines; Disease Models, Animal; Heart; Hyperglycemia; Hyperlipidemias; Hypertension; Inflammation; Insulin Resistance; Male; Malondialdehyde; Metabolic Syndrome; Obesity; Oxidative Stress; Rats; Rats, Zucker; Superoxide Dismutase

Increased methylglyoxal (MG) formation is associated with diabetes and its complications. In zebrafish, knockout of the main MG detoxifying system Glyoxalase 1, led to limited MG elevation but significantly elevated aldehyde dehydrogenases (ALDH) activity and aldh3a1 expression, suggesting the compensatory role of Aldh3a1 in diabetes. To evaluate the function of Aldh3a1 in glucose homeostasis and diabetes, aldh3a1

Topics: Aldehyde Dehydrogenase; Aldehydes; Animals; Diabetes Mellitus; Gene Knockout Techniques; Humans; Hyperglycemia; Zebrafish

BackgroundPremature birth occurs when nephrogenesis is incomplete and has been linked to increased renal pathologies in the adult. Metabolic factors complicating preterm birth may have additional consequences for kidney development. Here, we evaluated the effects of prematurity and hyperglycemia on nephrogenesis in premature baboons when compared with those in term animals.MethodsBaboons were delivered prematurely (67% gestation; n=9) or at term (n=7) and survived for 2-4 weeks. Preterm animals were classified by glucose control during the first 5 days of life: normoglycemic (PtN; serum glucose 50-100 mg/dl, n=6) and hyperglycemic (PtH; serum glucose 150-250 mg/dl, n=3). Kidneys were assessed histologically for glomeruli relative area, maturity, size, and overall morphology. Kidney lysates were evaluated for oxidative damage with 4-hydroxynonenal (4-HNE) antibody.ResultsHistological examination revealed decreased glomeruli relative area (P<0.05), fewer glomerular generations (P<0.01), and increased renal corpuscle area (P<0.001) in preterm compared with those in term animals. Numbers of apoptotic glomeruli were similar between groups. PtH kidneys exhibited reduced nephrogenic zone width (P<0.0001), increased numbers of mature glomeruli (P<0.05), and increased 4-HNE staining compared with those in PtN kidneys.ConclusionPrematurity interrupts normal kidney development, independent of glomerular cell apoptosis. When prematurity is complicated by hyperglycemia; kidney development shifts toward accelerated maturation and increased oxidative stress.

Topics: Aldehydes; Animals; Animals, Newborn; Apoptosis; Blood Glucose; Female; Hyperglycemia; Immunohistochemistry; Kidney; Kidney Glomerulus; Male; Nephrons; Organogenesis; Oxidative Stress; Papio; Premature Birth; Term Birth

Oxidative stress plays a causal role in diabetic embryopathy. Maternal diabetes induces heart defects and impaired transforming growth factor beta (TGFβ) signaling, which is essential for cardiogenesis. We hypothesize that mitigating oxidative stress through superoxide dismutase 1 (SOD1) overexpression in transgenic (Tg) mice reverses maternal hyperglycemia-impaired TGFβ signaling and its downstream effectors.. Day 12.5 embryonic hearts from wild-type (WT) and SOD1 overexpressing embryos of nondiabetic (ND) and diabetic mellitus (DM) dams were used for the detection of oxidative stress markers: 4-hydroxynonenal (4-HNE) and malondlaldehyde (MDA), and TGFβ1, 2, and 3, phosphor (p)-TGFβ receptor II (TβRII), p-phosphorylated mothers against decapentaplegic (Smad)2, and p-Smad3. The expression of 3 TGFβ-responsive genes was also assessed. Day 11.5 embryonic hearts were explanted and cultured ex vivo, with or without treatments of a SOD1 mimetic (Tempol; Enzo Life Science, Farmingdale, NY) or a TGFβ recombinant protein for the detection of TGFβ signaling intermediates.. Levels of 4-HNE and MDA were significantly increased by maternal diabetes, and SOD1 overexpression blocked the increase of these 2 oxidative stress markers. Maternal diabetes suppresses the TGFβ signaling pathway by down-regulating TGFβ1 and TGFβ3 expression. Consequently, phosphorylation of TβRII, Smad2, and Smad3, downstream effectors of TGFβ, and expression of 3 TGFβ-responsive genes were reduced by maternal diabetes, and these reductions were prevented by SOD1 overexpression. Treatment with Tempol or TGFβ recombinant protein restored high-glucose-suppressed TGFβ signaling intermediates and responsive gene expression.. Oxidative stress mediates the inhibitory effect of hyperglycemia in the developing heart. Antioxidants, TGFβ recombinant proteins, or TGFβ agonists may have potential therapeutic values in the prevention of heart defects in diabetic pregnancies.

Topics: Aldehydes; Animals; Female; Heart; Hyperglycemia; Malondialdehyde; Mice; Mice, Transgenic; Myocardium; Oxidative Stress; Phosphorylation; Pregnancy; Pregnancy in Diabetics; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad2 Protein; Smad3 Protein; Superoxide Dismutase; Superoxide Dismutase-1; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Transforming Growth Factor beta3

Dorsal root ganglia (DRG) sensory neurons cultured from 3 to 5 month streptozotocin (STZ)-induced diabetic rats exhibit structural and biochemical changes seen in peripheral nerve fibers in vivo, including axonal swellings, oxidative damage, reduced axonal sprouting, and decreased NF-κB activity. NF-κB is a transcription factor required by DRG neurons for survival and plasticity, and regulates transcription of antioxidant proteins (e.g. MnSOD). We hypothesized that the diabetes-induced decrease in NF-κB activity in DRG contributes to pathological phenomena observed in cultured DRG neurons from diabetic rats.. NF-κB localization was assessed in intact DRG and neuron cultures using immunostaining. NF-κB activity was manipulated in sensory neuron cultures derived from age-matched normal or 3-5 month STZ-diabetic rats using pharmacological means and lentiviral expression of shRNA. The impact of diabetes and altered NF-κB activity on neuronal phenotype involved analysis of neurite outgrowth, neurite morphology, oxidative stress (lipid peroxidation) and expression of MnSOD.. STZ-induced diabetes caused a significant decrease in nuclear localization of NF-κB subunits p50 and c-rel, but no change in p65 in intact DRG. Inhibition of NF-κB in normal neuron cultures significantly increased axonal swellings and oxidative stress, and reduced both neurite outgrowth and expression of MnSOD. These phenomena mimicked markers of pathology in cultured DRG neurons from diabetic rats. Enhancement of NF-κB activity in cultured diabetic DRG neurons ameliorated the sub-optimal neurite outgrowth and MnSOD levels triggered by diabetes. Exogenous insulin enhanced nuclear localization of p50 and c-rel but not p65 in diabetic neuronal cultures.. The diabetes-induced decrease of nuclear localization of NF-κB subunits p50 and c-rel in DRG contributes to development of in vitro markers of peripheral neuropathy, possibly through impaired mitochondrial ROS scavenging by deficient MnSOD.

Topics: Aldehydes; Analysis of Variance; Animals; ATPases Associated with Diverse Cellular Activities; Axons; Cells, Cultured; Diabetes Mellitus, Experimental; Disease Models, Animal; DNA Helicases; Ganglia, Spinal; GAP-43 Protein; Gene Expression Regulation; Green Fluorescent Proteins; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Neoplasm Proteins; Neurites; NF-kappa B; Nucleocytoplasmic Transport Proteins; Oxidative Stress; Rats; Rats, Sprague-Dawley; RNA, Small Interfering; Sensory Receptor Cells; Superoxide Dismutase; Time Factors; Transcription Factor RelA; Transfection

Oxidative stress plays a causative role in diabetic embryopathy. We tested whether mitigating oxidative stress, using superoxide dismutase 1 (SOD1) transgenic (Tg) mice, would block hyperglycemia-induced specific protein kinase C (PKC) isoform activation and its downstream cascade.. Day 8.5 embryos from nondiabetic wild-type control (NC), diabetic mellitus wild-type (DM), and diabetic SOD1-Tg mice (DM-SOD1-Tg) were used for detection of phosphorylated (p-) PKCα/βII and p-PKCδ, and levels of 2 prominent PKC substrates, phosphorylated myristoylated alanine-rich protein kinase C substrate (MARCKS) and receptor for activated C kinase 1 (RACK1), and lipid peroxidation markers, 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA).. Levels of p-PKCα/βII, p-PKCδ, p-MARCKS, 4-HNE, and MDA were significantly elevated in the DM group compared with those in the NC group and the DM-SOD1-Tg group. The NC and DM-SOD1-Tg groups had comparable levels of these protein and lipid peroxidation markers. RACK1 levels did not differ among the 3 groups.. Mitigating oxidative stress by SOD1 overexpression blocks maternal hyperglycemia-induced activation of specific PKC isoforms and downstream cascades.

Topics: Aldehydes; Animals; Diabetes Complications; Diabetes Mellitus, Experimental; Female; Fetal Diseases; Hyperglycemia; Intracellular Signaling Peptides and Proteins; Isoenzymes; Lipid Peroxidation; Male; Malondialdehyde; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myristoylated Alanine-Rich C Kinase Substrate; Neuropeptides; Pregnancy; Protein Kinase C; Protein Kinase C beta; Protein Kinase C-alpha; Protein Kinase C-delta; Receptors for Activated C Kinase; Superoxide Dismutase; Superoxide Dismutase-1

Previous studies show that polyunsaturated fatty acids (PUFAs) increase the insulin secretory capacity of pancreatic β-cells. We aimed at identifying PUFA-derived mediators and their cellular targets that are involved in the amplification of insulin release from β-cells preexposed to high glucose levels.. The content of fatty acids in phospholipids of INS-1E β-cells was determined by lipidomics analysis. High-performance liquid chromatography was used to identify peroxidation products in β-cell cultures. Static and dynamic glucose-stimulated insulin secretion (GSIS) assays were performed on isolated rat islets and/or INS-1E cells. The function of peroxisome proliferator-activated receptor-δ (PPAR-δ) in regulating insulin secretion was investigated using pharmacological agents and gene expression manipulations.. High glucose activated cPLA(2) and, subsequently, the hydrolysis of arachidonic and linoleic acid (AA and LA, respectively) from phospholipids in INS-1E cells. Glucose also increased the level of reactive oxygen species, which promoted the peroxidation of these PUFAs to generate 4-hydroxy-2E-nonenal (4-HNE). The latter mimicked the GSIS-amplifying effect of high glucose preexposure and of the PPAR-δ agonist GW501516 in INS-1E cells and isolated rat islets. These effects were blocked with GSK0660, a selective PPAR-δ antagonist, and the antioxidant N-acetylcysteine or by silencing PPAR-δ expression. High glucose, 4-HNE, and GW501516 also induced luciferase expression in a PPAR-δ-mediated transactivation assay. Cytotoxic effects of 4-HNE were observed only above the physiologically effective concentration range.. Elevated glucose levels augment the release of AA and LA from phospholipids and their peroxidation to 4-HNE in β-cells. This molecule is an endogenous ligand for PPAR-δ, which amplifies insulin secretion in β-cells.

Topics: Aldehydes; Animals; Cell Line; Diabetes Mellitus, Type 2; Fatty Acids, Unsaturated; Gene Silencing; Gerbillinae; Group IV Phospholipases A2; Humans; Hyperglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Lipid Peroxidation; Male; PPAR delta; Rats; Rats, Wistar; Reactive Oxygen Species; Recombinant Proteins; Signal Transduction; Tissue Culture Techniques

The mechanisms underlying diabetic encephalopathy, are largely unknown. Here, we examined whether docosahexaenoic acid (DHA) and lutein could attenuate the oxidative changes of the diabetic cerebral cortex. The levels of malondialdehyde (MDA) were significantly increased and glutathione (GSH) and glutathione peroxidase activity (GPx) were decreased in diabetic rats. The number of 4-hydroxynonenal (4-HNE) positive cells was increased. Treatment with insulin, lutein or DHA and the combination of each antioxidant with insulin, significantly restored all markers concentrations mentioned above, and the increase in 4-HNE inmunofluorescence. We combined 4-HNE immunofluorescence with NeuN (Neuronal Nuclei) staining. The latter demonstrated extensive overlap with the 4-HNE staining in the cortex from diabetic rats. Our findings demonstrate a clear participation of glucose-induced oxidative stress in the diabetic encephalopathy, and that the cells suffering oxidative stress are neurons. Lowering oxidative stress through the administration of different antioxidants may be beneficial for the central nervous tissue in diabetes.

Topics: Aldehydes; Animals; Antigens, Nuclear; Antioxidants; Biomarkers; Brain Diseases, Metabolic; Cerebral Cortex; Diabetes Complications; Diabetes Mellitus, Experimental; Disease Models, Animal; Docosahexaenoic Acids; Drug Therapy, Combination; Fluorescent Antibody Technique; Glucose; Glutathione; Glutathione Peroxidase; Hyperglycemia; Insulin; Lipid Peroxidation; Lutein; Male; Malondialdehyde; Nerve Tissue Proteins; Oxidative Stress; Rats; Rats, Wistar; Treatment Outcome

Hyperglycemia is one of the major factors for hemorrhagic transformation after ischemic stroke. In this study, we tested the effect of hydrogen gas on hemorrhagic transformation in a rat focal cerebral ischemia model. Sprague-Dawley rats (n=72) were divided into the following groups: sham; sham treated with hydrogen gas (H(2)); Middle Cerebral Artery Occlusion (MCAO); and MCAO treated with H(2) (MCAO+H(2)). All rats received an injection of 50% dextrose (6 ml/kg i.p.) and underwent MCAO 15 min later. Following a 90 min ischemic period, hydrogen was inhaled for 2 h during reperfusion. We measured the level of blood glucose at 0 h, 0.5 h, 4 h, and 6 h after dextrose injection. Infarct and hemorrhagic volumes, neurologic score, oxidative stress (evaluated by measuring the level of 8 Hydroxyguanosine (8OHG), 4-Hydroxy-2-Nonenal (HNE) and nitrotyrosine), and matrix metalloproteinase (MMP)-2/MMP-9 activity were measured at 24 h after ischemia. We found that hydrogen inhalation for 2 h reduced infarct and hemorrhagic volumes and improved neurological functions. This effect of hydrogen was accompanied by a reduction of the expression of 8OHG, HNE, and nitrotyrosine and the activity of MMP-9. Furthermore, a reduction of the blood glucose level from 500+/-32.51 to 366+/-68.22 mg/dl at 4 h after dextrose injection was observed in hydrogen treated animals. However, the treatment had no significant effect on the expression of ZO-1, occludin, collagen IV or aquaporin4 (AQP4). In conclusion, hydrogen gas reduced brain infarction, hemorrhagic transformation, and improved neurological function in rats. The potential mechanisms of decreased oxidative stress and glucose levels after hydrogen treatment warrant further investigation.

Topics: Administration, Inhalation; Aldehydes; Animals; Antioxidants; Aquaporin 4; Brain Damage, Chronic; Cerebral Hemorrhage; Disease Progression; Drug Evaluation, Preclinical; Extracellular Matrix Proteins; Glucose; Hydrogen; Hyperglycemia; Infarction, Middle Cerebral Artery; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neuroprotective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Tyrosine

The Otsuka Long-Evans Tokushima fatty (OLETF) rat is a model of hyperphagic obesity in which the animals retain the desire to run voluntarily. Running wheels were provided for 4-wk-old OLETF rats for 16 wk before they were killed 5 h (WL5), 53 h (WL53), or 173 h (WL173) after the wheels were locked. Sedentary (SED) OLETF rats that were not given access to running wheels served as age-matched cohorts. Epididymal fat pad mass, adipocyte volume, and adipocyte number were 58%, 39%, and 47% less, respectively, in WL5 than SED rats. Contrary to cessation of daily running in Fischer 344 x Brown Norway rats, epididymal fat did not increase during the first 173 h of running cessation in the OLETF runners. Serum insulin and glucose levels were 77% and 29% less, respectively, in WL5 than SED rats. Oil red O staining for intramyocellular lipid accumulation was not statistically different among groups. However, lipid peroxidation levels, as determined by total trans-4-hydroxy-2-nonenal (4-HNE) and 4-HNE normalized to oil red O, was higher in epitrochlearis muscles of SED than WL5, WL53, and WL173 rats. mRNA levels of glutathione S-transferase-alpha type 4, an enzyme involved in cellular defense against electrophilic compounds such as 4-HNE, were higher in epitrochlearis muscle of WL53 than WL173 and SED rats. In contrast, 4-HNE levels in omental fat were unaltered. Epitrochlearis muscle palmitate oxidation and relative transcript levels for peroxisome proliferator-activated receptor-delta and peroxisome proliferator-activated receptor-gamma coactivator type 1 were surprisingly not different between runners and SED rats. In summary, voluntary running was associated with lower levels of lipid peroxidation in skeletal muscle without significant changes in intramyocellular lipids or mitochondrial markers in OLETF rats at 20 wk of age. Therefore, even in a genetic animal model of extreme overeating, daily physical activity promotes improved health of skeletal muscle.

Topics: Adipose Tissue; Aging; Aldehydes; Animals; Blood Glucose; Disease Models, Animal; Eating; Glutathione Transferase; Hyperglycemia; Hyperinsulinism; Insulin; Isoenzymes; Lipid Peroxidation; Male; Mitochondria, Muscle; Muscle, Skeletal; Obesity; Oxidation-Reduction; Palmitic Acid; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Physical Exertion; PPAR gamma; Rats; Rats, Inbred BN; Rats, Inbred F344; Rats, Inbred OLETF; RNA-Binding Proteins; RNA, Messenger; Running; Species Specificity; Superoxide Dismutase; Transcription Factors; Weight Gain

Reactive oxygen species are involved in a diversity of biological phenomena such as inflammation, carcinogenesis, aging, and atherosclerosis. We and other investigators have shown that the level of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker for oxidative stress, is increased in either the urine or the mononuclear cells of the blood of type 2 diabetic patients. However, the association between type 2 diabetes and oxidative stress in the pancreatic beta-cells has not been previously described. We measured the levels of 8-OHdG and 4-hydroxy-2-nonenal (HNE)-modified proteins in the pancreatic beta-cells of GK rats, a model of nonobese type 2 diabetes. Quantitative immunohistochemical analyses with specific antibodies revealed higher levels of 8-OHdG and HNE-modified proteins in the pancreatic beta-cells of GK rats than in the control Wistar rats, with the levels increasing proportionally with age and fibrosis of the pancreatic islets. We further investigated whether the levels of 8-OHdG and HNE-modified proteins would be modified in the pancreatic beta-cells of GK rats fed with 30% sucrose solution or 50 ppm of voglibose (alpha-glucosidase inhibitor). In the GK rats, the levels of 8-OHdG and HNE-modified proteins, as well as islet fibrosis, were increased by sucrose treatment but reduced by voglibose treatment. These results indicate that the pancreatic beta-cells of GK rats are oxidatively stressed, and that chronic hyperglycemia might be responsible for the oxidative stress observed in the pancreatic beta-cells.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Blood Glucose; Deoxyguanosine; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Hyperglycemia; Immunohistochemistry; Inositol; Insulin; Islets of Langerhans; Oxidative Stress; Proteins; Rats; Rats, Inbred Strains; Solutions; Sucrose