bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression and synthesis of TGFβ1 is induced in macrophages by 9‐oxononanoyl cholesterol, a major cholesteryl ester oxidation product
Authors: Sottero Barbara , Gamba Paola , Longhi Monica , Robbesyn Fanny , Abuja Peter M. , Schaur Rudolf J. , Poli Giuseppe , Leonarduzzi Gabriella 
Published: December 2008

AbstractWithin the broad variety of compounds generated via oxidative reactions in low density lipoproteins (LDL) and subsequently found in the atherosclerotic plaque, are aldehydes still esterified to the parent lipid and termed core‐aldehydes. The most represented cholesterol core‐aldehyde in LDL is 9‐oxononanoyl cholesterol (9‐ONC), an oxidation product of cholesteryl linoleate. Here we report that 9‐ONC, at concentration actually detectable in biological material, significantly up‐regulates the expression and the synthesis of the pro‐fibrogenic cytokine transforming growth factor β1 (TGFβ1) by cultured macrophages. As previously demonstrated for other lipid oxidation products present in LDL, namely a biologically representative mixture of oxysterols and the unesterified aldehyde 4‐hydroxynonenal, these effects on TGFβ1 by 9‐ONC further points to LDL lipid oxidation as a powerful source of pro‐fibrogenic stimuli.
Possible involvement of 4‐hydroxynonenal in splenocyte regulated liver regeneration
Authors: Cipak Ana , Borovic Suzana , Scukanec‐Spoljar Mira , Kirac Iva , Zarkovic Neven 
Published: December 2008

AbstractLiver regeneration is a complex, systemic process regulated by humoral and cellular mechanisms. Inflammatory response to the extensive tissue damage, as in partial hepatectomy, plays important role during regeneration. Hence, it is assumed that the spleen might play a role in systemic inflammatory response involved in liver regeneration. On the other hand, liver damage and consequential regeneration are often associated with oxidative stress and lipid peroxidation. One of the end products of lipid peroxidation, 4‐hydroxynonenal (HNE), is nowadays considered not only as a “second toxic messenger of free radicals“ but also as a growth‐regulating factor. We therefore studied in vitro interactions of the HNE‐treated murine liver cells and autologous spleen cells. The spleen cells supported recovery of liver cells from the HNE cytotoxicity although spleen cells themselves exerted cytotoxic effects against the proliferating liver cells that were not treated with HNE. Our results imply that the cytokines secreted by activated immunocompetent cells may be responsible for the observed recovery of the HNE‐damage liver cells, suggesting that HNE might be an important factor regulating cellular and cytokine mediated mechanisms of liver regeneration control.
Role of 4‐hydroxy‐2,3‐nonenal in the pathogenesis of fibrosis
Authors: Chiarpotto Elena , Castello Laura , Leonarduzzi Gabriella , Biasi Fiorella , Poli Giuseppe 
Published: December 2008

AbstractTransient activation of fibroblasts or fibroblast‐like cells to proliferate and to produce elevated quantities of extracellular matrix is essential to fibrosis. This activation is regulated by several cytokines produced by various inflammation‐associated cells. Among these, transforming growth factor beta1 (TGFβ1) is considered of major importance. Many studies have shown that lipid peroxidation play a key role in the initiation and progression of fibrosis in different organs. In fact, 4‐hydroxy‐2,3‐nonenal (HNE), the major aldehydic product of lipid peroxidation, is able to induce TGFβ1 expression and synthesis, and activation of activator protein‐1 (AP‐1) transcription factor. In this study, using the murine macrophage line J774‐A1, we show that these effects are strictly related to the chemical structure of HNE, since neither 2‐nonenal nor nonanal are biologically active to the same extent. Moreover, we demonstrate that HNE can indeed contribute to the onset of fibrosis by stimulating AP‐1 binding to DNA and consequently inducing TGFβ1 expression, since thiol‐group reagents, such as N‐ethylmaleimide and 4‐(chloro‐mercuri)‐benzenesulfonic acid, that down‐modulate HNE entrance and localisation inside the cell, prevent both phenomena.The possibility to control fibrogenic cytokine levels by means of antioxidant or dietetic treatments opens new potential pharmacological and nutritional horizons in the treatment of many chronic diseases characterised by excessive fibrosis.
4‐Hydroxynonenal and TGF‐β1 concur in inducing antiproliferative effects on the Caco‐2 human colon adenocarcinoma cell line
Authors: Vizio Barbara , Poli Giuseppe , Chiarpotto Elena , Biasi Fiorella 
Published: December 2008

Abstract4‐Hydroxynonenal (HNE) has been demonstrated to exert its antiproliferative effect by up‐regulating the c‐Jun‐N‐terminal kinase (JNK), a member of the mitogen‐activated protein kinase family (MAPKs). Transforming growth factor‐β1 (TGF‐β1) is the major negative regulatory factor in controlling cell proliferation, and Smads are its intracellular transducers. Recent data on human colon adenocarcinoma has shown a low HNE content paralleled by a marked alteration of TGF‐β1 levels within the tumor mass. The two events appear related because of the demonstrated marked ability of HNE to up‐regulate expression and synthesis of TGF‐β1; the combined decreases of HNE and TGF‐β1 found in cancer cells provide a favorable condition for neoplastic progression. Furthermore, HNE is likely able to interact with the cytokine to enhance apoptosis and increase intracellular reactive oxygen species (ROS) formation in the Caco‐2 colon carcinoma cell line.The probable mechanism whereby HNE and TGF‐β1 interact to induce apoptosis is through cross‐talk between the main signaling pathways of the two molecules (JNK and Smads), and the observed ROS production might only contribute to amplifying the apoptotic pathways. The network between the two signaling pathways here involved is now under investigation.
Iron uptake of the normoxic, anoxic and postanoxic microglial cell line RAW 264.7
Authors: Widmer Rebecca , Grune Tilman 
Published: December 2008

AbstractIron is one of the trace elements playing a key role in the normal brain metabolism. An excess of free iron on the other hand is catalyzing the iron‐mediated oxygen radical production. Such a condition might be a harmful event leading perhaps to serious tissue damage and degeneration. Therefore, during evolution a complex iron sequestering apparatus developed, minimizing the amount of redox‐reactive free iron. However, this system might be severely disturbed under pathophysiological conditions including hypoxia or anoxia.Since little is known about the non‐transferrin‐mediated iron metabolism of the brain during anoxia/reoxygenation, we tested the ability of the microglial cell line RAW 264.7 to take up iron independently of transferrin under various oxygen concentrations. Microglial cells are thought to be the major player in the maintenance of the extracellular homeostasis in the brain. Therefore, we investigated the iron metabolism of microglial cells employing radiolabeled ferric chloride. We tested the uptake of iron under normoxic, anoxic and postanoxic conditions. Furthermore, the amount of ferritin was measured by immunoblotting. We were able to show that iron enters the microglial cell line in the absence of extracellular transferrin under normoxic, anoxic and postanoxic conditions. Interestingly, the amount of ferritin is decreasing in the early reoxygenation phase.Therefore, we concluded that microglia is able to contribute to the brain iron homeostasis under anoxic and postanoxic conditions.
Copper related toxic effects on cellular protein metabolism in human astrocytes
Authors: Merker Katrin , Hapke Doreen , Reckzeh Kristian , Schmidt Hartmut , Lochs Herbert , Grune Tilman 
Published: December 2008

AbstractIntroduction: Copper overload due to a defect in the ATPase 7B mediated copper excretion within hepatocytes produces the phenotype of Wilson disease. The overload of hepatocytes with copper results in necrotic liver cells and is accompanied by a high concentration of blood copper levels. That occurs to be the reason for increasing neurological copper concentration. Although copper is linked to oxidation, there are no data on the direct copper related effects in human brain cells.Aim: To test the copper induced changes in protein oxidation in human astrocyte like cells.Methods: We used U87 cells as model for human astrocytes. Cells were treated with increasing concentrations of copper(II)‐chloride in Dulbeccos minimal essential medium. Subsequently, at different time points we investigated: cellular growth, cellular survival under copper treatment, the concentration of oxidized tryptophane in GADPH in vitro as well as the carbonyl concentration and the concentration of oxidized proteins in vivo in U87 glial cells.Results: The viability of cells decreased with both increasing copper concentration and duration of treatment. The concentration of oxidized proteins was directly correlated to the increase of copper concentration and duration of exposure.Conclusion: These observations demonstrate the similarities between copper treatment and treatment with other commonly used oxidants, including hydrogen peroxide. Furthermore, the vulnerability of astrocytes towards copper exposure could be demonstrated. Therefore, these data give further insights into understanding of copper metabolism, which in turn is important to reveal the exact pathological mechanism in copper related diseases such as Wilson disease.
Role of 4‐hydroxynonenal in the hemozoin‐mediated inhibition of differentiation of human monocytes to dendritic cells induced by GM‐CSF/IL‐4
Authors: Skorokhod Oleksii , Schwarzer Evelin , Grune Tilman , Arese Paolo 
Published: December 2008

AbstractIn falciparum malaria, rupture of parasitized RBC liberates hemozoin (HZ), polymerized heme that contains and generates lipoperoxidation products. In HZ and HZ‐loaded monocytes 4‐HNE attained approx. 50 and 15 μM, respectively. In malaria, HZ‐loaded monocytes are precursors of dendritic cells (DC). Here, the role of 4‐HNE as inhibitor of DC differentiation was examined. 4‐HNE in HZ was quantified after derivatization by HPLC. DC were differentiated in vitro from human monocytes supplemented with GM‐CSF/IL‐4 and analyzed for surface antigens and 4‐HNE‐adducts by FACScan after labelling with specific antibodies. HZ‐loading, or treatment with 4‐HNE induced large numbers of 4‐HNE‐protein‐adducts on the monocyte membrane. As low as 10 nM 4‐HNE inhibited up‐regulation of functionally important DC differentiation markers. 1 μM 4‐HNE elicited inhibition of up‐regulation of DC differentiation markers as follows: MHC‐class I and II, −29% and −40%; CD1a, −16%; CD40, −25%; CD54, −27%; and CD83 (the most important DC differentiation marker), −45%, with no signs of apoptosis. The sequence of additions was important, as the inhibitory effect was reduced when 4‐HNE was added after GM‐CSF/IL‐4, indicating that GM‐CSF/IL‐4 receptors could be modified by 4‐HNE. In conclusion, inhibition of DC differentiation by 4‐HNE may play a role in malaria immunodepression.
HNE‐dependent molecular damage in diabetic nephropathy and its possible prevention by N‐acetyl‐cysteine and oxerutin
Authors: Furfaro Anna Lisa , Menini Stefano , Patriarca Stefania , Pesce Carlo , Odetti Patrizio , Cottalasso Damiano , Marinari Umberto M. , Adelaide Pronzato M. , Traverso Nicola 
Published: December 2008

AbstractAccumulation of Advanced Lipoxidation End‐products (ALE), such as MDA‐ and HNE‐protein adducts, and Advanced Glycation End‐products, such as carboxymethyl‐lysine (CML), are probably involved in the development of diabetic nephropathy. In this study the effect of some antioxidant treatments (oxerutin, N‐acetylcysteine, taurine and N‐acetylcysteine+taurine) on kidney lipoxidative damage has been evaluated by immunohistochemistry in streptozotocined rats.Diabetic rats showed marked glomerular positivity for ALE, while the samples from Control rats were negative. All treatments except taurine were able to protect the glomeruli from ALE accumulation; the failure of taurine may be due to residual oxidative properties of its derivatives. These data are consistent with those of our previous study, which showed that all the antioxidants used except taurine protected the glomeruli from diabetes‐induced enlargement, increased apoptotic rate, decreased cell density and CML accumulation.These data attest to a role of glycoxidative and lipoxidative damage in diabetes‐dependent damage of the kidney, and indicate that specific antioxidants can prevent or attenuate diabetic nephropathy.
Supercomplex organization of the mitochondrial respiratory chain and the role of the Coenzyme Q pool: Pathophysiological implications
Authors: Genova Maria Luisa , Bianchi Cristina , Lenaz Giorgio 
Published: December 2008

AbstractIn this review we examine early and recent evidence for an aggregated organization of the mitochondrial respiratory chain. Blue Native Electrophoresis suggests that in several types of mitochondria Complexes I, III and IV are aggregated as fixed supramolecular units having stoichiometric proportions of each individual complex. Kinetic evidence by flux control analysis agrees with this view, however the presence of Complex IV in bovine mitochondria cannot be demonstrated, presumably due to high levels of free Complex. Since most Coenzyme Q appears to be largely free in the lipid bilayer of the inner membrane, binding of Coenzyme Q molecules to the Complex I‐III aggregate is forced by its dissociation equilibrium; furthermore free Coenzyme Q is required for succinate‐supported respiration and reverse electron transfer. The advantage of the supercomplex organization is in a more efficient electron transfer by channelling of the redox intermediates and in the requirement of a supramolecular structure for the correct assembly of the individual complexes. Preliminary evidence suggests that dilution of the membrane proteins with extra phospholipids and lipid peroxidation may disrupt the supercomplex organization. This finding has pathophysiological implications, in view of the role of oxidative stress in the pathogenesis of many diseases.
C. elegansknockouts in ubiquinone biosynthesis genes result in different phenotypes during larval development
Authors: Gavilán ÁNgela , Asencio Claudio , Cabello Juan , Rodríguez‐Aguilera Juan C. , Schnabel Ralf , Navas PlÁCido 
Published: December 2008

AbstractUbiquinone is an essential molecule in aerobic organisms to achieve both, ATP synthesis and antioxidant defence. Mutants in genes responsible of ubiquinone biosynthesis lead to non‐respiringpetiteyeast. In C. elegans,coq‐7/clk‐1but notcoq‐3mutants live longer than wild type showing a ‘slowed’ phenotype.In this paper we demonstrate that absence in ubiquinone in coq‐1, coq‐2 or coq‐8 mutants lead to larval development arrest, slowed pharyngeal pumping, eventual paralysis and cell death. All these features emerge during larval development, whereas embryo development appeared similar to that of wild type individuals. Dietary coenzyme Q did not restore any of the alterations found in thesecoqmutants.These phenomena suggest that coenzyme Q mutants unable to synthesize this molecule develop a deleterious phenotype leading to lethality. On the contrary, phenotype ofC. elegans coq‐7/clk‐1mutants may be a unique phenotype than can not generalize to mutants in ubiquinone biosynthesis. This particular phenotype may not be based on the absence of endogenous coenzyme Q, but to the simultaneous presence of dietary coenzyme Q and the its biosynthesis intermediate demethoxy‐coenzyme Q.
NAD+/NADH and/or CoQ/CoQH2 ratios from plasma membrane electron transport may determine ceramide and sphingosine‐1‐phosphate levels accompanying G1 arrest and apoptosis
Authors: Luca Thomas De , Morré Dorothy M. , Zhao Haiyun , James Morré D. 
Published: December 2008

AbstractTo elucidate possible biochemical links between growth arrest from antiproliferative chemotherapeutic agents and apoptosis, our work has focused on agents (EGCg, capsaicin, cis platinum, adriamycin, anti‐tumor sulfonylureas, phenoxodiol) that target tNOX. tNOX is a cancer‐specific cell surface NADH oxidase (ECTO‐NOX protein), that functions in cancer cells as the terminal oxidase for plasma membrane electron transport. When tNOX is active, coenzyme Q10 (ubiquinone) of the plasma membrane is oxidized and NADH is oxidized at the cytosolic surface of the plasma membrane. However, when tNOX is inhibited and plasma membrane electron transport is diminished, both reduced coenzyme Q10 (ubiquinol) and NADH would be expected to accumulate. To relate inhibition of plasma membrane redox to increased ceramide levels and arrest of cell proliferation in G1 and apoptosis, we show that neutral sphingomyelinase, a major contributor to plasma membrane ceramide, is inhibited by reduced glutathione and ubiquinone. Ubiquinol is without effect or stimulates. In contrast, sphingosine kinase, which generates anti‐apoptotic sphingosine‐1‐phosphate, is stimulated by ubiquinone but inhibited by ubiquinol and NADH. Thus, the quinone and pyridine nucleotide products of plasma membrane redox, ubiquinone and ubiquinol, as well as NAD+ and NADH, may directly modulate in a reciprocal manner two key plasma membrane enzymes, sphingomyelinase and sphingosine kinase, potentially leading to G1 arrest (increase in ceramide) and apoptosis (loss of sphingosine‐1‐phosphate). As such, the findings provide potential links between coenzyme Q10‐mediated plasma membrane electron transport and the anticancer action of several clinically‐relevant anticancer agents.
Coenzyme Q10 in maternal plasma and milk throughout early lactation
Authors: Niklowitz Petra , Menke Thomas , Giffei JÖRg , Andler Werner 
Published: December 2008

AbstractIn contrast to other lipophilic antioxidants Coenzyme Q10 originates from food intake as well as from endogenous synthesis. The CoQ10 concentration and lipid content of maternal milk and maternal plasma was investigated during early lactation.Breast milk was obtained from 23 women: A: colostrums (24–48 hours postpartum), B: transitional milk (day 7 pp), C: mature milk (day 14 pp). At the same time capillary blood specimens were collected. Milk and plasma were stored at −84°C until CoQ10 was analysed after hexane extraction by HPLC. The lipid content was determined by PAP‐analysis of cholesterol.The plasma content of CoQ10 was the highest soon after delivery (A: 1.29, B:1.20, C:1.07 pmol/μl; Wilcoxon p<0.05 A vs. C and B vs. C). This tendency was still evident after lipid‐adjustment (A:209, B:180, C:175 μmol CoQ10/mol cholesterol; Wilcoxon p<0.01 A vs. B and C). The level of CoQ10 in milk showed a gradual decline during early lactation (A:0.80, B:0.57, C:0.44 pmol/μl; Wilcoxon p<0.02 A vs. B and C). After lipid‐adjustment this tendency became even more evident (A: 137, B:86, C:67 μmol CoQ10/mol cholesterol; Wilcoxon p<0.002 A vs. B and C, p<0.05 B vs. C). The content of CoQ10 in plasma and milk showed a correlation with early milk (Spearman p<0.005) but not with mature milk.Although lipid content is low the colostrums is a rich source for the lipophilic antioxidant CoQ10.
Ubiquinol and the papaverine derivative caroverine prevent the expression of tumour‐ promoting factors in adenoma and carcinoma colon cancer cells induced by dietary fat
Authors: Nohl Hans , Rohr‐Udilova Natalia , Gille Lars , Bieberschulte Werner , Jurek Daniela , Marian Brigitte , Schulte‐Hermann Rolf 
Published: December 2008

AbstractHigh consumption of dietary fat promotes colon carcinogenesis. While this effect is well known the underlying mechanism is not understood. Fatty acid hydroperoxides (LOOH) arise from unsaturated fatty acids in the presence of oxygen and elevated temperature during food processing. An approach was made starting from the assumption that LOOH are present in dietary fats as a result of boiling. LOOH undergoes homolytic cleavage in the presence of iron. We studied their effects on gene expression in colorectal tumour cells using linoleic acid hydroperoxide (LOOH) as model compound. Addition to the medium of LT97 adenoma and SW480 carcinoma cells enhanced the production of hydrogen peroxide. Both cell lines were observed to increase VEGF and COX‐II expression based on mRNA. Expression of VEGF was inhibited by caroverine and ubiquinon.
Coenzyme Q10 protects SHSY5Y neuronal cells from beta amyloid toxicity and oxygen‐glucose deprivation by inhibiting the opening of the mitochondrial permeability transition pore
Authors: Li Geng , Zou Liang‐Yu , Cao Chun‐Mei , Yang Edward S. 
Published: December 2008

AbstractCoenzyme Q10 (CoQ10) is an essential biological cofactor which increases brain mitochondrial concentration and exerts neuroprotective effects. In the present study, we exposed SHSY5Y neuroblastoma cells to neurotoxic beta amyloid peptides (Aβ) and oxygen glucose deprivation (OGD) to investigate the neuroprotective effect of 10μM CoQ10 by measuring (i) cell viability by the MTT assay, (ii) opening of the mitochondrial permeability transition pore via the fluorescence intensity of calcein‐AM, and (iii) superoxide anion concentration by hydroethidine. Cell viability (mean ± S.E.M.) was 55.5 ± 0.8% in the group exposed to Aβ + OGD, a value lower than that in the Aβ or OGD group alone (P<0.01). CoQ10 had no neuroprotective effect on cell death induced by either Aβ or OGD, but increased cell survival in the Aβ + OGD group to 57.3 ± 1.7%, which was higher than in the group treated with vehicle (P<0.05). The neuroprotective effect of CoQ10 was blocked by administration of 20μM atractyloside. Pore opening and superoxide anion concentration were increased in the Aβ + OGD group relative to sham control (P<0.01), and were attenuated to the sham level (P>0.05) when CoQ10 was administered. Our results demonstrate that CoQ10 protects neuronal cells against Aβ neurotoxicity together with OGD by inhibiting the opening of the pore and reducing the concentration of superoxide anion.
Muscle coenzyme Q10 concentrations in patients with probable and definite diagnosis of respiratory chain disorders
Authors: Montero R. , Artuch R. , Briones P. , Nascimento A. , García‐Cazorla A. , Vilaseca M.A. , Śnchez‐Alćzar J.A. , Navas P. , Montoya J. , Pineda M. 
Published: December 2008

AbstractCoenzyme Q10 (CoQ) deficiency syndrome is a disorder of unknown ethiology that may cause different forms of mitochondrial encephalomyopathy. In the present study our aim was to analyse CoQ concentration and mitochondrial respiratory chain (MRC) enzyme activities in muscle biopsies of patients with clinical suspicion and/or biochemical‐molecular diagnosis of a mitochondrial disorder. We studied 36 patients classified into 3 groups: 1) 14 patients without a definitive diagnosis of mitochondrial disease, 2) 13 patients with decreased CI+III and II+III activities of the MRC, and 3) 9 patients with definitive diagnosis of mitochondrial disease. Only 1 of the 14 patients of group 1 showed slightly reduced CoQ values in muscle. Six of the 13 patients from group 2 showed partial CoQ deficiency in muscle and 1 of the 9 cases from group 3 presented a slight CoQ deficiency. Significantly positive correlation was observed between CI+III and CII+III activities with CoQ concentrations in the 36 muscle homogenates from patients (r=0.555; p=0.001; and r=0.460; p=0.005, respectively). In conclusion, measurement of MRC enzyme activities is a useful tool for the detection of CoQ deficiency, which should be confirmed by CoQ quantification.