4-hydroxy-2-nonenal and Anemia

Oxidative stress plays an important role in the pathogenesis of falciparum malaria, a disease still claiming close to 1 million deaths and 200 million new cases per year. Most frequent complications are severe anemia, cerebral malaria, and immunodepression, the latter being constantly present in all forms of malaria. Complications are associated with oxidative stress and lipoperoxidation. Its final product 4-hydroxynonenal (4-HNE), a stable yet very reactive and diffusible molecule, forms covalent conjugates with proteins, DNA, and phospholipids and modulates important cell functions at very low concentrations. Since oxidative stress plays important roles in the pathogenesis of severe malaria, it appears important to explore the role of 4-HNE in two important malaria complications such as malaria anemia and malaria immunodepression where oxidative stress is considered to be involved. In this review we will summarize data about 4-HNE chemistry, its biologically relevant chemical properties, and its role as regulator of physiologic processes and as pathogenic factor. We will review studies documenting the role of 4-HNE in severe malaria with emphasis on malaria anemia and immunodepression. Data from other diseases qualify 4-HNE both as oxidative stress marker and as pathomechanistically important molecule. Further studies are needed to establish 4-HNE as accepted pathogenic factor in severe malaria.

Topics: Aldehydes; Anemia; Dendritic Cells; Erythrocytes; Humans; Lipid Peroxidation; Malaria

Converging in vitro evidence and clinical data indicate that oxidative stress may play important roles in Plasmodium falciparum malaria, notably in the pathogenesis of severe anaemia. However, oxidative modifications of the red blood cell (RBC)-membrane by 4-hydroxynonenal (4-HNE) and haemoglobin-binding, previously hypothesized to contribute mechanistically to the pathogenesis of clinical malaria, have not yet been tested for clinical significance. In 349 non-immune Mozambican newborns recruited in a double-blind placebo-controlled chemoprophylaxis trial, oxidative markers including 4-HNE-conjugates and membrane-bound haemoglobin were longitudinally assessed from 2·5 to 24 months of age, at first acute malaria episode and in convalescence. During acute malaria, 4-HNE-conjugates were shown to increase significantly in parasitized and non-parasitized RBCs. In parallel, advanced oxidation protein products (AOPP) rose in plasma. 4-HNE-conjugates correlated with AOPP and established plasma but not with RBC oxidative markers. High individual levels of 4-HNE-conjugates were predictive for increased malaria incidence rates in children until 2 years of life and elevated 4-HNE-conjugates in convalescence accompanied sustained anaemia after a malaria episode, indicating 4-HNE-conjugates as a novel patho-mechanistic factor in malaria. A second oxidative marker, haemoglobin binding to RBC-membranes, hypothesized to induce clearing of RBCs from circulation, was predictive for lower malaria incidence rates. Further studies will show whether or not higher membrane-haemoglobin values at the first malaria episode may provide protection against malaria.

Topics: Aldehydes; Anemia; Antigens, Protozoan; Antimalarials; Artemisinins; Biomarkers; Child, Preschool; Double-Blind Method; Endemic Diseases; Erythrocytes; Humans; Infant; Malaria, Falciparum; Mozambique; Oxidative Stress; Pyrimethamine; Sulfadoxine

Severe anaemia is a life-threatening complication of falciparum malaria associated with loss of predominantly non-parasitized red blood cells (npRBCs). This poorly elucidated process might be influenced by (i) rosettes, i.e. npRBCs cytoadherent to haemozoin-containing parasitized RBCs (pRBCs) and (ii) generation in pRBCs of 4-hydroxynonenal (4-HNE) through haemozoin-catalysed lipid peroxidation. We explored whether close proximity in rosettes may facilitate 4-HNE transfer to npRBCs, which is likely to enhance their phagocytosis and contribute to malaria anaemia. Fluorescence microscopy and flow cytometry data indicated 4-HNE transfer to npRBCs in rosettes. Rosettes were formed by 64·8 ± 1·8% varO-expressing pRBCs, and 8·7 ± 1·1% npRBCs were positive for 4-HNE-protein-conjugates, while low-rosetting parasites generated only 2·4 ± 1·1% 4-HNE-conjugate-positive npRBCs. 4-HNE transfer decreased after blocking rosetting by monoclonal antibodies. A positive linear relationship between rosette frequency and 4-HNE-conjugates in npRBCs was found in 40 malaria patients, a first indication for a role of rosetting in npRBCs modifications in vivo. Children with severe malaria anaemia had significantly higher percentages of 4-HNE-conjugate-positive npRBCs compared to children with uncomplicated malaria. In conclusion, 4-HNE transfer from pRBCs to npRBCs in rosettes is suggested to play a role in the phagocytic removal of large numbers of npRBCs, the hallmark of severe malaria anaemia.

Topics: Aldehydes; Anemia; Biological Transport; Cell Line; Child; Child, Preschool; Erythrocytes; Female; Hemeproteins; Humans; Infant; Lipid Peroxidation; Malaria, Falciparum; Male; Plasmodium falciparum

Patients with end-stage renal failure undergoing haemodialysis (HD) are exposed to oxidative stress. Increased levels of malondialdehyde (MDA) were demonstrated in plasma of uraemic patients, indicating accelerated lipid peroxidation (LPO) as a consequence of multiple pathogenetic factors. The aim of our investigation was to examine the role of renal anaemia in oxidative stress in HD patients.. MDA and 4-hydroxynonenal (HNE) were measured in three groups of patients undergoing HD: group I comprised eight patients with a blood haemoglobin (Hb) < 10 g/dl (mean Hb = 8.1+/-1.3 g/dl), and group II were eight patients with a Hb > 10 g/dl (mean Hb=12.4+/-1.9g/dl); none of these 16 patients had been treated with human recombinant erythropoietin (rHuEpo). Group III comprised 27 patients with a mean Hb of 10.5+/-1.6 g/dl after long-term rHuEpo treatment.. Mean plasma concentrations of both MDA and HNE were significantly higher (P<0.0001) in all 43 HD patients than in 20 healthy controls (MDA 2.85+/-0.25 vs 0.37+/-0.03 microM, HNE 0.32+/-0.03 vs 0.10+/-0.01 microM). Comparing the three groups, it was shown that HD patients with a Hb <10 g/dl had significantly higher plasma levels of LPO products (MDA 3.81+/-0.86 microM, HNE 0.45+/-0.07 microM) than HD patients with a Hb >10g/dl (MDA 2.77+/-0.58 UM, HNE 0.25+/-0.05 microM), and than HD patients treated with rHuEpo (MDA 2.50+/-0.12 microM, HNE 0.29+/-0.03 microM). Furthermore, an inverse correlation between plasma concentration of LPO products and haemoglobin levels was seen (r=0.62, P<0.0001).. Radical generation in HD patients might be caused in part by renal anemia itself. Treatment with rHuEpo may decrease radical generation effectively in HD patients due to the increase in the number of red blood cells and blood haemoglobin concentration.

Topics: Adult; Aged; Aged, 80 and over; Aldehydes; Anemia; Erythrocyte Count; Erythropoietin; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Recombinant Proteins; Renal Dialysis; Retrospective Studies

Chronic exposure to arsenic in rats led to gradual accumulation of the toxicant in erythrocytes causing oxidative stress in these cells. 4-Hydroxynonenal (4-HNE), a major aldehyde product of lipid peroxidation, contributed significantly to the cytopathological events observed during oxidative stress in the erythrocytes of exposed rats. 4-HNE triggered death signal cascade that was initiated with the formation of HNE-protein adducts in cytosol. HNE-protein adduct formation resulted in depletion of cytosolic antioxidants followed by increased generation of ROS. Results showed accumulation of hydrogen peroxide (H(2)O(2)) from the early stages of arsenic exposure, while superoxide (O(2)(*-)) and hydroxyl radical ((*)OH) also contributed to the oxidative stress during longer period of exposure. Suppression of antioxidant system coupled with increased generation of ROS eventually led to activation of caspase 3 during arsenic exposure. Attenuation of HNE-mediated activation of caspase 3 in presence of N-acetylcysteine (NAC) indicated the involvement of GSH in the process. Prevention of HNE-mediated degradation of membrane proteins in presence of Z-DEVD-FMK identified caspase 3 as the principal mediator of HNE-induced cellular damage during arsenic exposure. Degradation of band 3 followed by its aggregation on the red cell surface promoted immunologic recognition of redistributed band 3 by autologous IgG with subsequent attachment of C3b. Finally, the formation of C3b-IgG-band 3 immune complex accelerated the elimination of affected cells from circulation and led to the decline of erythrocyte life span during chronic arsenic toxicity.

Topics: Aldehydes; Anemia; Animals; Arsenic; Caspase 3; Environmental Pollutants; Enzyme Activation; Erythrocytes; Hydrogen Peroxide; Hydroxyl Radical; Male; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxides; Toxicity Tests, Chronic

Recombinant human erythropoetin beta; (rHuEPO) has not only an erythropoietic effect but also appears to affect production of cytokines and may improve nutritional status of dialysis patients. Darbepoetin alpha; is a new erythropoiesis-stimulating protein with a threefold longer serum half-life when compared with rHuEPO. The objective of this prospective study was to assess oxidative stress, inflammation, nutrition and hematological response in peritoneal dialysis (PD) patients who were switched from rHuEPO beta to darbepoetin alpha. 12 stable PD patients (6 M, 6 F; mean age 56.2 +/- 15.1 yr.) were evaluated during this study together with 22 healthy volunteers serving as a control group. All patients had been receiving erythropoetin beta subcutaneously once a week before they were reassigned to darbepoetin. The new drug was administered every other week for 6 months, in a dose equivalent to a weekly dose of previously taken rHuEPO. Hematology, iron status and biochemical profiles were evaluated monthly. Markers of oxidative stress: malondialdehyde/ 4-hydroxynoneal (MDA/4HNE), carbonyl groups (CG), oxyLDL and AGEs and markers of inflammation: CRP, TNF alpha, IL-6 were measured on rHuEPO beta before the switch to darbepoetin, and after 1st and 6th month of darbepoetin treatment. The assessment of nutritional status was determined by body mass index (BMI), serum albumin concentration and Subjective Global Assessment (SGA).. Mean levels of Hb and Hct were stable during 6 months of observation and not significantly different from the data observed for on rHuEPO. Nutritional status was good in 9 patients, 3 patients were malnourished at the beginning of this study as assessed by SGA and this status persisted to the end of observation. The levels of markers of oxidative stress and inflammation were statistically higher than in the control group (p < 0.05).. Darbepoetin alpha given subcutaneously once every 2 weeks is effective for the treatment of anemia in PD patients. Less frequent administration of darbepoetin has a biological response similar to weekly administration of rHuEPO.

Topics: Adult; Aldehydes; Anemia; Biomarkers; C-Reactive Protein; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Follow-Up Studies; Hematinics; Humans; Inflammation; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Malondialdehyde; Middle Aged; Nutritional Status; Oxidative Stress; Peritoneal Dialysis; Prospective Studies; Recombinant Proteins; Serum Albumin; Time Factors; Treatment Outcome

Severe malaria anemia is characterized by inhibited/altered erythropoiesis and presence of hemozoin-(HZ)-laden bone-marrow macrophages. HZ mediates peroxidation of unsaturated fatty acids and production of bioactive aldehydes such as 4-hydroxynonenal (HNE). HZ-laden human monocytes inhibited growth of cocultivated human erythroid cells and produced HNE that diffused to adjacent cells generating HNE-protein adducts. Cocultivation with HZ or treatment with low micromolar HNE inhibited growth of erythroid cells interfering with cell cycle without apoptosis. After HZ/HNE treatment, 2 critical proteins in cell-cycle regulation, p53 and p21, were increased and the retinoblastoma protein, central regulator of G₁-to-S-phase transition, was consequently hypophosphorylated, while GATA-1, master transcription factor in erythropoiesis was reduced. The resultant decreased expression of cyclin A and D2 retarded cell-cycle progression in erythroid cells and the K562 cell line. As a second major effect, HZ and HNE inhibited protein expression of crucial receptors (R): transferrinR1, stem cell factorR, interleukin-3R, and erythropoietinR. The reduced receptor expression and the impaired cell-cycle activity decreased the production of cells expressing glycophorin-A and hemoglobin. Present data confirm the inhibitory role of HZ, identify HNE as one HZ-generated inhibitory molecule and describe molecular targets of HNE in erythroid progenitors possibly involved in erythropoiesis inhibition in malaria anemia.

Topics: Aldehydes; Anemia; Biomarkers; Cell Cycle; Cell Differentiation; Cell Line; Cell Proliferation; Coculture Techniques; Colony-Forming Units Assay; Cyclin A; Cyclin D2; Cyclin-Dependent Kinase Inhibitor p21; Erythroid Cells; Erythropoiesis; GATA1 Transcription Factor; Glycophorins; Hemeproteins; Hemoglobins; Humans; Malaria; Monocytes; Receptors, Immunologic; Tumor Suppressor Protein p53

Malarial anemia involves destruction of parasitized and non-parasitized red blood cells and dyserythropoiesis. Malarial pigment, hemozoin (HZ), is possibly implicated in dyserythropoiesis. We show that supernatants of HZ and HZ-fed-monocytes, and 4-hydroxynonenal generated by them, inhibited progenitor growth.

Topics: Aldehydes; Anemia; Animals; Cells, Cultured; Erythropoiesis; Hemeproteins; Humans; Malaria; Plasmodium

Patients with end-stage renal disease undergoing hemodialysis (HD) are exposed to oxidative stress. Increased levels of malondialdehyde (MDA) and 4-hydroxylnonenal (HNE) were found in plasma of uremic patients indicating accelerated lipid peroxidation (LPO) as a consequence of multiple pathogenetic factors. The catabolism and action of those products was already intensively studied. As highly reactive metabolites they are able to bind to proteins, nucleic acids, and other molecules. Doing so, they exert molecular signal effects in cells and are able to exacerbate tissue and organ damage, e.g. cardiotoxic effects. Since renal anemia was shown to promote oxidative stress as well, the aim of our investigation was to examine its role in HD patients. Therefore, two groups of HD patients were investigated (group I Hb < 10 g/dl, group II Hb > 10 g/dl) and serum concentrations of MDA, HNE, and of protein carbonyls, a marker for protein oxidation, were determined. All HD patients had significantly higher levels of the LPO products MDA and HNE compared with controls. However, group I patients showed higher MDA and HNE concentrations compared to group II patients. The same result could be seen for protein carbonyls. During HD concentration of both LPO products decreased. However, this was not the case for protein carbonyls. These results lead to the conclusion that optimized correction of the renal anemia may result in a significant reduction of oxidative stress and therefore in the reduction of organ tissue damage. In this way correction of renal anemia will reduce the cardiovascular risk and comorbidity of HD patients improving their prognosis.

Topics: Aldehydes; Anemia; Cardiovascular Diseases; Female; Humans; Kidney Failure, Chronic; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Oxidation-Reduction; Oxidative Stress; Proteins; Renal Dialysis; Risk Factors

Homocysteine serum levels were measured in patients with end-stage renal disease in relation to severity of renal anemia and oxidative stress parameters such as 4-hydroxynonenal (HNE) and malondialdehyde (MDA). The predialytic homocysteine serum levels of the patients are five times as high as in healthy controls. It was found that homocysteine does not correlate to hemoglobin concentration and to oxidative stress, but rather to parameters of nutrition status such as albumine concentration and protein catabolic rate. The homocysteine accumulation represents a cardiovascular risk factor which is statistically independent of oxidative stress, but dependent on nutrition or energy status in patients with chronic renal failure.

Topics: Aldehydes; Anemia; Cardiovascular Diseases; Female; Hemoglobins; Homocysteine; Humans; Kidney Failure, Chronic; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Renal Dialysis; Risk Factors