High Dose Fish Oil Added to Various Lipid Emulsions Normalizes Superoxide Dismutase 1 Activity in Home Parenteral Nutrition Patients.

(1) Objectives: Intestinal failure in home parenteral nutrition patients (HPNPs) results in oxidative stress and liver damage. This study investigated how a high dose of fish oil (FO) added to various lipid emulsions influences antioxidant status and liver function markers in HPNPs. (2) Methods: Twelve HPNPs receiving Smoflipid for at least 3 months were given FO (Omegaven) for a further 4 weeks. Then, the patients were randomized to subsequently receive Lipoplus and ClinOleic for 6 weeks or vice versa plus 4 weeks of Omegaven after each cycle in a crossover design. Twelve age- and sex-matched healthy controls (HCs) were included. (3) Results: Superoxide dismutase (SOD1) activity and oxidized-low-density lipoprotein concentration were higher in all baseline HPN regimens compared to HCs. The Omegaven lowered SOD1 compared to baseline regimens and thus normalized it toward HCs. Lower paraoxonase 1 activity and fibroblast growth factor 19 (FGF19) concentration and, on the converse, higher alkaline phosphatase activity and cholesten concentration were observed in all baseline regimens compared to HCs. A close correlation was observed between FGF19 and SOD1 in baseline regimens. (4) Conclusions: An escalated dose of FO normalized SOD1 activity in HPNPs toward that of HCs. Bile acid metabolism was altered in HPNPs without signs of significant cholestasis and not affected by Omegaven.

Fish oil supplementation with various lipid emulsions suppresses in vitro cytokine release in home parenteral nutrition patients: a crossover study.

Long-chain n-3 polyunsaturated fatty acids modulate immune cell functions. The primary objective of this study was to evaluate the impact of different lipid emulsions (LEs) with supplemented doses of fish oil (FO) on serum cytokine concentration and in vitro cytokine production in patients with intestinal failure on home parenteral nutrition (HPNPs). We hypothesized that FO supplementation would diminish lipopolysaccharide (LPS)-stimulated cytokine production. Twelve HPNPs receiving Smoflipid for at least 3 months were given FO (Omegaven) for a further 4 weeks. After this cycle, the patients were randomized to subsequently receive 1 cycle with Lipoplus and 1 cycle with ClinOleic for 6 weeks or vice versa plus 4 weeks of added Omegaven after each cycle in a crossover design. Comparison of the baseline LE regimens showed lower LPS-stimulated production of IL-1ß in the HPNPs on Lipoplus than on the Smoflipid and ClinOleic regimens, as well as lower IL-8 compared to the Smoflipid regimen. Omegaven reduced IL-8 concentration in serum under the Lipoplus regimen and diminished LPS-stimulated production of IL-1ß under the Smoflipid and ClinOleic. IL-6 and TNF-α production was depressed only in those on Smoflipid. Irrespective of the LE used, the HPNPs compared to the healthy controls showed higher IL-6, IL-8, and TNF-α concentrations in serum and LPS-stimulated production of IL-6 as well as lower n-6/n-3 long-chain polyunsaturated fatty acids in the erythrocyte phospholipids. LPS-stimulated production of IL-6 correlated negatively with the parenteral dose of eicosapentaenoic acid + docosahexaenoic acid. In conclusion, FO-supplemented parenteral nutrition suppresses in vitro cytokine production.

Placental Growth Factor in Bladder Cancer Compared to the Diagnostic Accuracy and Prognostic Performance of Vascular Endothelial Growth Factor A.

BACKGROUND/AIM: To evaluate the diagnostic accuracy and prognostic performance of urinary and plasma levels of placental growth factor (PLGF) and provide their comparison with the results of vascular endothelial growth factor A (VEGF-A) in patients with primary and recurrent urinary bladder cancer. MATERIALS AND METHODS: The enzyme-linked immunosorbent assay (ELISA) was used to assess urinary and plasma concentrations of PLGF and VEGF-A in 240 individuals. RESULTS: PLGF levels in urine and plasma were significantly higher in patients with primary bladder cancer than in healthy individuals (p=0.003, p=0.005, respectively). Area under the curve (AUC) of urinary PLGF was 0.68; AUC of plasma PLGF levels was 0.65. Patients with the urine levels of PLGF higher than 82.33 pg/ml had three times higher risk of recurrence. In patients with recurrent bladder cancer, the urinary concentrations of PLGF did not significantly differ from the concentrations in patients without current disease (p=0.61). However, plasma PLGF levels were significantly higher in patients diagnosed with tumor recurrence (p=0.001); AUC of plasma PLGF levels was 0.69. Moreover, patients with plasma levels higher than 10.09 pg/ml had a five-times higher risk of future tumor recurrence. The diagnostic accuracy of PLGF was comparable with VEGF-A. CONCLUSION: From a clinical point of view, PLGF could be considered a valid diagnostic test for the detection of primary and recurrent bladder cancer. In patients with recurrent bladder cancer, plasma PLGF levels can differentiate individuals at risk of tumor recurrence.

Osteopontin as a discriminating marker for pancreatic cancer and chronic pancreatitis.

INTRODUCTION: We analyzed concentrations of osteopontin (OPN) in patients with pancreatic ductal adenocarcinoma (PDAC) in order to determine firstly whether it is useful to distinguish between PDAC patients and those with chronic non-hereditary pancreatitis (CP) and type 2 diabetes mellitus (T2DM), and secondly whether OPN concentrations depend on the PDAC stage. METHODS: Groups consisting of 64 patients with PDAC, 71 with CP, 67 with T2DM and 48 healthy controls (CON) were enrolled in the study. Controls were compared with regard to levels of OPN, oxidative stress markers, conventional tumor markers and other biochemical parameters. RESULTS: Levels of OPN were higher in patients with PDAC compared with CP patients (P< 0.001), T2DM (P< 0.001) and CON (P< 0.001). There were increased OPN levels in CP patients in comparison with T2DM (P< 0.001) and CON (P< 0.001). Patients with PDAC in stage IV had higher OPN levels than PDAC patients in stage III (P< 0.01). There was no difference in OPN levels of PDAC patients in stage III compared to patients in stage II. CONCLUSION: Our pilot study demonstrates the usefulness of estimating OPN levels to differentiate between pancreatic cancer and chronic pancreatitis. Higher OPN levels over 102 ng/ml could be a potential diagnostic biomarker for pancreatic cancer.

Increased inflammatory markers with altered antioxidant status persist after clinical recovery from severe sepsis: a correlation with low HDL cholesterol and albumin.

Markers of oxidative stress and antioxidant status in relation to inflammatory mediators in septic patients (SPs) during the course of sepsis and after recovery were analysed. Patients were 30 critically ill adults in severe sepsis/septic shock, 19 of which completed 3 samplings (S1: within 24 h after onset of sepsis, S7: 7 days after S1, R7: 7 days after clinical recovery). Comparing SPs with healthy controls (HCs), enhanced C-reactive protein, procalcitonin, bilirubin and CuZn-superoxide dismutase activity were found at S1 only. Oxidized low-density lipoprotein, conjugated dienes and nitrotyrosine were increased at S1, culminated at S7 and reverted nearly to HC levels at R7. Reduced catalase activity and serum amyloid were observed at S1 and endured until R7. Increase in IL-6, IL-10 and tumour necrosis factor alpha (TNF-α) with accompanying decrease in apolipoprotein A1, high-density lipoprotein (HDL) cholesterol, selenium, zinc, albumin, paraoxonase 1 and glutathione peroxidase 1 activity appeared at S1 and persisted until R7. TNF-α, IL-10 and markers of oxidative stress were in negative correlation with HDL cholesterol and albumin at R7. After clinical recovery, increased cytokines and decreased antioxidants were accompanied by lower albumin and HDL cholesterol levels. During this important and beneficial period of tissue repair, patients with prolonged persistence of this status are probably more vulnerable to secondary infections and should be dealt with as constituting a high-risk population.

Antioxidant status and oxidative stress markers in pancreatic cancer and chronic pancreatitis.

OBJECTIVES: Oxidative stress has been implicated in the pathogenesis of chronic pancreatitis (CP) and pancreatic cancer (PC). The study aim was to assess the oxidative stress markers and antioxidant defense system in patients with CP and those with PC. METHODS: Activities of superoxide dismutase 1 (SOD1), catalase (CAT), glutathione peroxidase 1 (GPX1), glutathione reductase (GR), arylesterase (PON1-A) and lactonase (PON1-L) activities of paraoxonase 1 (PON1) and concentrations of reduced glutathione, conjugated dienes in low-density lipoprotein (CD/LDL) and oxidized LDL (ox-LDL/LDL) were assessed in 50 PC and 50 CP patients and 50 age and sex-matched controls. RESULTS: Comparison of PC and CP groups to controls found the following changes: glutathione peroxidase 1 (GPX1) (-20.2%, -25.5%; P < 0.001), glutathione reductase (GR) (-9.5%, -11.9%; P < 0.05), SOD1 (+22.9%; P < 0.01), CAT (-10.6%; P < 0.05), PON1-A (-34.3%, -16.0%; P < 0.001), PON1-L (-44.2%; -17.0%; P < 0.01), conjugated dienes in LDL (CD/LDL) (+20%, +33.3%; P < 0.05) and ox-LDL/LDL (+42.2%, +14.4%; P < 0.05). The patients with PC had changed activities and levels of SOD1 (+24.2%), CAT (-10.4); P < 0.01), PON1-A (-21.7%), PON1-L (-32.9%), and ox-LDL/LDL (+24.3%); (all P < 0.01) compared with the patients with CP. CONCLUSIONS: Reduced antioxidant defense system capacity and increased markers of oxidative stress were found in PC and CP. PON1-L and CAT activities, along with ox-LDL/LDL levels, were the independent factors differentiating the patients with PC from the patients with CP.

Altered activities of antioxidant enzymes in patients with metabolic syndrome.

OBJECTIVE: In the pathogenesis of the metabolic syndrome (MetS), an increase of oxidative stress could play an important role which is closely linked with insulin resistance, endothelial dysfunction, and chronic inflammation. The aim of our study was to assess several parameters of the antioxidant status in MetS. METHODS: 40 subjects with MetS and 40 age- and sex-matched volunteers without MetS were examined for activities of superoxide dismutase (CuZnSOD), catalase (CAT), glutathione peroxidase 1 (GPX1), glutathione reductase (GR), paraoxonase1 (PON1), concentrations of reduced glutathione (GSH), and conjugated dienes in low-density lipoprotein (CD-LDL). RESULTS: Subjects with MetS had higher activities of CuZnSOD (p < 0.05) and GR (p < 0.001), higher concentrations of CD-LDL (p < 0.001), lower activities of CAT (p < 0.05) and PON1 (p < 0.05), and lower concentrations of GSH (p < 0.05), as compared with controls. Activity of GPX1 was not significantly changed. CONCLUSIONS: Our results implicated an increased oxidative stress in MetS and a decreased antioxidative defense that correlated with some laboratory (triglycerides, high-density lipoprotein cholesterol (HDL-C)) and clinical (waist circumference, blood pressure) components of MetS.

[Oxidative stress after anthracycline therapy in patients with solid tumors]. / Oxidacní stres u nemocných po lécbe antracyklíny pro solidní nádorová onemocnení

BACKGROUND: Anthracyclines are regarded as some of the most potent oxidative stress inductors. Despite the fact that oxidative stress induction by anthracyclines is believed to be the key factor in anthracycline-related cardiotoxicity, the precise timeline of oxidative stress changes after anthracycline treatment remains unknown. The aim of the present study is to assess the level of oxidative stress after anthracycline therapy in patients with solid tumors. PATIENTS: The study population consists of 128 adult patients (14 males, 114 females, mean age 56 ± 10 years) receiving anthracycline chemotherapy for solid tumors. The control group consists of 38 patients (4 males, 34 females, mean age 59 ± 11 years) receiving anthracycline-free chemotherapy for solid tumors. METHODS: The main activities of antioxidant enzymes (catalase, glutathione peroxidase-1, superoxide dismutase, and paraoxonase-1) and concentrations of conjugated dienes, surrogate markers of oxidative stress level, were established at the baseline and after anthracycline therapy (median 45; IQR 27-69 days after the end of anthracycline therapy) in all patients. By comparing the activities of antioxidant enzymes and the concentrations of conjugated dienes, before and after therapy, changes in oxidative stress level within the time period were established for both study groups. Differences between the study groups, with regard to changes in the activities of antioxidant enzymes and the concentrations of conjugated dienes, were also evaluated. CONCLUSIONS: An increase in oxidative stress was observed after the end of anthracycline therapy in patients with solid tumors. However, our study shows that this persistent elevation of oxidative stress after the end of anthracycline therapy is probably not caused by anthracyclines.

N-3 polyunsaturated fatty acids in the treatment of atherogenic dyslipidemia.

BACKGROUND: Atherogenic dyslipidemia contributes substantially to the residual cardiovascular risk. The aim of this study was to examine the effects of therapeutic doses of n-3 polyunsaturated fatty acids on the three major lipid abnormalities of atherogenic dyslipidemia, i.e. hypertriacylglycerolemia, low HDL cholesterol, and increased levels of small dense LDL particles, as well as on some new risk factors. MATERIALS AND METHODS: A total of 60 hypertriacylglycerolemic patients were included in the study. Group S consisted of 36 patients who were already treated with statins, Group N of 24 patients not yet treated. Each patient was examined after six weeks on placebo and six weeks of treatment with n-3 PUFA (eicosapentaenoic and docosahexaenoic acid ethyl esters, 3.0 g/d). RESULTS: Treatment with n-3 PUFA caused a decrease in plasma triacylglycerols (28%, p<0.001), and VLDL (-27%, p<0.001), an increase in HDL-C (+4%, p<0.01), and a decrease in sdLDL cholesterol (-16%, p<0.05). These changes were accompanied by a decrease in microalbuminuria (-30%, p<0.05), as well as in several parameters of oxidative stress. Analysis of the fatty acids composition of plasma phospholipids showed a significant increase in all n-3 PUFAs examined, accompanied by a decrease in n-6 PUFAs, as well as in monounsaturated acids. No significant differences in the effects of n-3 PUFA were found between the Groups S and N. CONCLUSION: Our results support the opinion that hypertriacylglycerolemic patients benefit from the treatment with n-3 PUFA which improves several important metabolic factors of cardiovascular risk.

[Reactive oxygen and nitrogen species in the clinical medicine]. / Reaktivní kyslíkové a dusíkové slouceniny v klinické medicíne.

Vast knowledge has accumulated recently on the role of reactive oxygen and nitrogen species (RONS) in clinical medicine. Strong evidence was disclosed on their important role in the pathogenesis of several diseases. Free radicals have unpaired electron and this is the reason for extreme reactivity causing propagation reactions that lead to the multiple damage to cells. Oxidizing agents belong to the family of reactive species. Reactive oxygen species are produced during biochemical processes such as oxidative phosphorylation, phagocytosis and metabolism of purins. Overproduction of reactive oxygen species can cause the tissue damage. Reactive nitrogen species are produced by inhibition of nitric oxide synthase by the action of asymmetric dimethylarginine. Peroxisomal oxidases, NAD(P) oxidase, xanthinoxidase, nitric oxide synthase, myeloperoxidase and lipooxygenase catalyze biochemical reactions producing reactive oxygen and nitrogen species. Biochemical and molecular processes in cells are negatively influenced by chemical modification of DNA, proteins and lipids caused by the action of reactive oxygen and nitrogen species. Antioxidant metabolites and enzymes work together to stop and to prevent oxidative modification of biomolecules. Reactive oxygen and nitrogen species play an important role in the pathogenesis of many diseases such as atherosclerosis, diabetes, hyperlipidaemia and neurodegenerative diseases.

[Alterations in fatty acid composition of plasma and erythrocyte lipids in critically ill patients during sepsis]. / Zmeny ve slození mastných kyselin v lipidech plazmy a erytrocytu u kriticky nemocných v prubehu sepse.

BACKGROUND: The overall fatty acid (FA) composition, and especially proportions of n-6 and n-3 polyunsaturated fatty acids in plasma and membrane lipids, greatly impacts on cell and organ functions as well as on many biological processes. MATERIAL AND METHODS: Polyunsaturated FA determine membrane fluidity and thus modulate activities of membrane proteins (enzymes, carriers and receptors). They also are precursors of pro- and anti-inflammatory eicosanoids and other autacoids (resolvins, protectins). Thus, alterations in lipid FA composition of critically ill patients affect reactivity of the organism to numerous pathological stimuli. The objective of this study was to analyse FA composition of plasma triacylglycerols, cholesteryl esters, plasma phospholipids and erythrocyte phospholipids in septic patients. RESULTS: The study group consisted of 30 septic patients, 19 of whom were available for three samplings: Sampling 1 was 24 hours after the onset of sepsis, Sampling 2 was 7 days after Sampling 1, and Sampling 3 was 7 days after recovery from sepsis. Eight septic patients died. Compared to healthy controls, a decrease in n-6 polyunsaturated fatty acids accompanied by increase in monounsaturated fatty acids in cholesteryl esters, plasma phospholipids and erythrocyte phospholipids persisted in all three samplings of septic patients. CONCLUSIONS: This effect of sepsis was significantly greater in cholesteryl esters and plasma phospholipids of non-surviving septic patients than in surviving ones. Moreover, non-survivors had lower proportions of n-3 polyunsaturated fatty acids in plasma phospholipids compared to survivors. The significant decrease in proportion of polyunsaturated fatty acids in lipids of septic patients in the course of sepsis reflects the severity of their critical state and supports the importance of appropriate nutritional polyunsaturated fatty acids supplementation.

Decreased paraoxonase activity in critically ill patients with sepsis.

Paraoxonase 1 is believed to play a role in preventing lipid oxidation and, thus, limiting production of proinflammatory mediators. Systemic inflammatory response in sepsis increases oxidative stress and decreases high-density lipoprotein (HDL) concentrations. The objective of this study was to investigate serum paraoxonase 1 activities in critically ill patients with sepsis and after recovery. Serum paraoxonase 1 arylesterase/paraoxonase activities, concentration of total cholesterol, HDL cholesterol (HDL-C) and serum C-reactive protein (CRP) in septic patients of a medical intensive care unit (n = 30) and age/sex-matched outpatient controls without sepsis (n = 30) were analyzed. Paired convalescent samples were also taken 1 week after recovery (n = 11). In septic patients, both arylesterase (88.3 +/- 36.5 vs. 162.1 +/- 44.8 kU/l, P < 0.001) and paraoxonase (75.2 +/- 50.0 vs. 125.2 +/- 69.4 U/l, P < 0.01) paraoxonase 1 activities decreased as compared to controls. Both activities normalized after recovery. Negative correlation was found between CRP and both arylesterase (r = -0.676, P < 0.001) and paraoxonase (r = -0.401, P < 0.01) as well as positive correlation between HDL-C and both arylesterase (r = 0.585, P < 0.001) and paraoxonase (r = 0.405, P < 0.01) paraoxonase 1 activities. The decreased activity of paraoxonase 1 in negative correlation with CRP offers a potentially useful marker of sepsis progress and recovery in critically ill patients.

Antioxidative enzymes and increased oxidative stress in depressive women.

OBJECTIVES: To investigate the activities of the main antioxidative enzymes and oxidative stress in women with depressive disorder (DD). METHODS: In 35 drug-naive women with DD and 35 age matched healthy women enzymes superoxide dismutase (CuZnSOD), catalase (CAT), glutathione peroxidase (GPX1), glutathione reductase (GR) and paraoxonase (PON1), concentrations of conjugated dienes (CD), reduced glutathione (GSH) and anthropometric and clinical data were investigated. RESULTS: Women with DD were found to have decreased activities of GPX1 (p<0.05), decreased concentrations of GSH (p<0.05), and increased activities of GR (p<0.05), CuZnSOD (p<0.001), and concentrations of CD (p<0.05). Activity of GPX1 was positively correlated with concentration of GSH (p<0.05). Concentrations of CD were positively correlated with TG (p<0.01). CONCLUSION: Our set of depressive women was characterized by changes indicating an increased oxidative stress, as well as by certain features of metabolic syndrome.

Severity of metabolic syndrome unfavorably influences oxidative stress and fatty acid metabolism in men.

Metabolic syndrome (MS) is defined by the clustering of several components (MSC), which include abdominal fat accumulation, impaired glucose homeostasis, hypertriglyceridemia, lowered high-density lipoprotein cholesterol, increased blood pressure, and hyperuricemia. Metabolic syndrome is also accompanied by increased oxidative stress and inflammation as well as by altered composition of esterified fatty acids (FA). Therefore, we have investigated 210 men (categorized into six groups with increasing number of MSC) to find trends in the extent of oxidative stress, FA pattern and frequency of pathological alleles of the selected candidate genes for lipid metabolism. Increasing number of MSC was connected with the raised serum glucose and insulin, increased concentrations of conjugated dienes in low-density lipoprotein (all p < 0.0001), and high frequency of e2 and e4 alleles of the apolipoprotein E gene (p < 0.005). However, the last significance was lost after the adjustment for age. The incidence of 54Thr allele for intestinal isoform of the fatty acid-binding protein (FABP-2) gene was comparable in all groups. The most important findings were the raised content of saturated FA and the increased activities of Delta9 and Delta6 desaturases (all p < 0.0001), and the decreased content of polyunsaturated FA n-6 family and the decreased activity of Delta5 desaturase (both p < 0.001) in connection with increasing number of MSC. In conclusion, the severity of MS is connected with the progression of oxidative stress and the unfavorable changes in the FA composition. These changes are independent of the studied gene polymorphisms.