Peroxiredoxin-1 aggravates lipopolysaccharide-induced septic shock via promoting inflammation.

Septic shock induced by lipopolysaccharide (LPS) is characterized by serious systemic inflammatory response and robust production of pro-inflammatory cytokines from activated macrophages. Damage-associated molecular patterns (DAMPs) secreted by activated macrophages are key contributors to septic shock. However, the current knowledge on those DAMPs that promote inflammatory response under LPS-induced septic shock remains poorly understood. Here, we report that Peroxiredoxin 1 (Prdx1) plays a detrimental role in LPS-induced septic shock. Intraperitoneal injection of LPS elicited a progressive course of septic shock in mice, which was characterized by significant lethality along with robust production of cytokines (IL-1ß, IL-6 and TNF-α). Removal of Prdx1 strongly protected mice from LPS-induced death, and decreased IL-1ß, IL-6 and TNF-α productions. Additionally, primary macrophages deficient in Prdx1 are less able to produce much more IL-1ß, IL-6 and TNF-α. Collectively, we provide a demonstration for Prdx1 contributing to LPS-induced septic shock likely via promoting inflammation.

Blood-based gene expression profile of oxidative stress and antioxidant genes for identifying surrogate markers of liver tissue injury in chronic hepatitis C patients.

Oxidative stress is the process by which reactive molecules and free radicals are formed in cells. In this study, we report the blood-based gene expression profile of oxidative stress and antioxidant genes for identifying surrogate markers of liver tissue in chronic hepatitis C (CHC) patients by using real-time PCR. A total of 144 untreated patients diagnosed with CHC having genotype 3a and 20 healthy controls were selected for the present study. Liver biopsy staging and grading of CHC patients were performed using the METAVIR score. Total RNA was extracted from liver tissue and blood samples, followed by cDNA synthesis and real-time PCR. The relative expression of genes was calculated using the ΔΔCt method. The expression profile of 84 genes associated with oxidative stress and antioxidants was determined in liver tissue and blood samples. In liver tissue, 46 differentially expressed genes (upregulated, 27; downregulated, 19) were identified in CHC patients compared to normal samples. In blood, 61 genes (upregulated, 51; downregulated; 10) were significantly expressed in CHC patients. A comparison of gene expression in liver and whole blood showed that 20 genes were expressed in a similar manner in the liver and blood. The expression levels of commonly expressed liver and blood-based genes were also correlated with clinical factors in CHC patients. A receiver operating curve (ROC) analysis of oxidative stress genes (ALB, CAT, DHCR24, GPX7, PRDX5, and MBL2) showed that infections in patients with CHC can be distinguished from healthy controls. In conclusion, blood-based gene expression can reflect the behavior of oxidative stress genes in liver tissue, and this blood-based gene expression study in CHC patients explores new blood-based non-invasive biomarkers that represent liver damage.

Plasma peroxiredoxin changes and inflammatory cytokines support the involvement of neuro-inflammation and oxidative stress in Autism Spectrum Disorder.

BACKGROUND: It has been established that children with Autism Spectrum Disorders (ASD) are affected by oxidative stress, the origin of which is still under investigation. In the present work, we evaluated inflammatory and pro-oxidant soluble signature in non-syndromic ASD and age-matched typically developing (TD) control children. METHODS: We analyzed leukocyte gene expression of inflammatory cytokines and inflammation/oxidative-stress related molecules in 21 ASD and 20 TD children. Moreover, in another-comparable-group of non-syndromic ASD (N = 22) and TD (N = 21) children, we analyzed for the first time the protein expression of the four members of the antioxidant enzyme family of peroxiredoxins (Prx) in both erythrocyte membranes and in plasma. RESULTS: The gene expression of IL6 and of HSP70i, a stress protein, was increased in ASD children. Moreover, gene expression of many inflammatory cytokines and inflammation/oxidative stress-related proteins correlated with clinical features, and appeared to be linked by a complex network of inter-correlations involving the Aryl Hydrocarbon Receptor signaling pathway. In addition, when the study of inter-correlations within the expression pattern of these molecules was extended to include the healthy subjects, the intrinsic physiological relationships of the inflammatory/oxidative stress network emerged. Plasma levels of Prx2 and Prx5 were remarkably increased in ASD compared to healthy controls, while no significant differences were found in red cell Prx levels. CONCLUSIONS: Previous findings reported elevated inflammatory cytokines in the plasma of ASD children, without clearly pointing to the presence of neuro-inflammation. On the other hand, the finding of microglia activation in autoptic specimens was clearly suggesting the presence of neuro-inflammation in ASD. Given the role of peroxiredoxins in the protection of brain cells against oxidative stress, the whole of our results, using peripheral data collected in living patients, support the involvement of neuro-inflammation in ASD, and generate a rational for neuro-inflammation as a possible therapeutic target and for plasma Prx5 as a novel indicator of ASD severity.

Identification and characterization of peroxiredoxin 1 from Lateolabrax japonicus under biotic and abiotic stresses.

The peroxiredoxins (Prxs) belong to a novel and evolutionarily conserved superfamily, which can protect cells from oxidative damage caused by ROS and play a vital role in immune responses. In the present study, a 995 base pairs (bp) Prx1 cDNA sequence (LjPrx1) with an open reading frame of 594 bp, which encoding 197 amino acid polypeptides was obtained from L. japonicus. Transcriptional expression analysis indicated that the LjPrx1 mRNA was ubiquitously expressed in all tissues tested, while a comparatively high expression level was detected in head-kidney and blood. After the recombinant LjPrx1 protein was acquired using a prokaryotic expression method, the antioxidant activity was assessed by the catalyzing hydrogen peroxide assay method, and the results showed that the recombinant LjPrx1 possessed an antioxidant activity in a temperature-dependent manner. To further study the function roles of LjPrx1 related to biotic and abiotic stresses, the head-kidney and blood were chosen for the following experiments, and a positive correlation between the expression of LjPrx1 and the different stresses was detected using qRT-PCR. In conclusion, this study provides useful information about the role of the LjPrx1 gene in defense against a variety of toxic factors in L. japonicus, which would broaden our current knowledge of Prx1.

[Concentration of proinflammatory cytokines, peroxiredoxin-1 and glutathione peroxidase activity in the blood plasma of patients with coronary artery disease undergoing coronary artery bypass grafting].

76 patients with coronary heart disease (who had undergone coronary artery bypass grafting) were examined to investigate the role of pro-inflammatory cytokines and enzymes involved in redox regulation, in the mechanisms of development of systemic inflammatory response syndrome. Patients were divided into 2 groups: 1st - patients with coronary heart disease, who as a result of clinical trials has not been set postpericardiotomy syndrome; 2nd - patients with coronary heart disease who have been diagnosed postpericardiotomy syndrome. The blood plasma of both groups indicated intensification of production of interleukin-6, intrleukin-8, as well as - an imbalance in the peroxiredoxin-1 and glutathione peroxidase. These changes by patients with postpericardiotomy syndrome are observed at the earliest time and differed depth of expression. The results of this work confirm the high potential of the investigated indicators for prevention and monitoring postpericardiotomy syndrome development.

Peroxiredoxin 1 induces inflammatory cytokine response and predicts outcome of cardiogenic shock patients necessitating extracorporeal membrane oxygenation: an observational cohort study and translational approach.

BACKGROUND: Extracellular peroxiredoxin 1 (Prdx1) has been implicated to play a pivotal role in regulating inflammation; however, its function in tissue hypoxia-induced inflammation, such as severe cardiogenic shock patients, has not yet been defined. Thus, the objective of this study was to test the hypothesis that Prdx1 possesses prognostic value and instigates systemic inflammatory response syndrome in cardiogenic shock patients undergoing extracorporeal membrane oxygenation (ECMO) support. METHODS: We documented the early time course evolution of circulatory Prdx1, hypoxic marker carbonic anhydrase IX, inflammatory cytokines including IL-6, IL-8, IL-10, MCP-1, TNF-α, IL-1ß, and danger signaling receptors (TLR4 and CD14) in a cohort of cardiogenic shock patients within 1 day after ECMO support. In vitro investigations employing cultured murine macrophage cell lines and human monocytes were applied to clarify the relationship between Prdx1 and inflammatory response. RESULTS: Prdx1 not only peaked earlier than all the other cytokines we studied during the initial course, but also predicted a worse outcome in patients who had higher initial Prdx1 plasma levels. The Prdx1 levels in patients positively correlated with hypoxic markers carbonic anhydrase IX and lactate, and inflammatory cytokines. In vitro study demonstrated that hypoxia/reoxygenation induced Prdx1 release from human monocytes and enhanced the responsiveness of the monocytes in Prdx1-induced cytokine secretions. Furthermore, functional inhibition by Prdx1 antibody implicated a crucial role of Prdx1 in hypoxia/reoxygenation-induced IL-6 secretion. CONCLUSIONS: Prdx1 release during the early phase of ECMO support in cardiogenic shock patients is associated with the development of systemic inflammatory response syndrome and poor clinical outcomes. Thus, circulating Prdx1 provides not only prognostic information but may be a promising target against ischemia/reperfusion injury.

Increased peroxiredoxin 4 levels in patients with prediabetes compared to normal glucose tolerance subjects.

BACKGROUND: Peroxiredoxin 4 is a part of endogen antioxidant system and its levels are elevated in oxidative stress conditions. Its levels are positively associated with cardiovascular risk. The aim of this study was to compare serum peroxiredoxin 4 levels between obese subjects with prediabetes and with normal glucose tolerance. METHODS: In this study, we included 80 patients with mean age 50·4 ± 10·6 years and divided them into two age and BMI-matched groups - group 1 with obesity without glycaemic disturbances (n = 41) and group 2 with obesity and prediabetes (n = 39). Oral glucose tolerance test with measurement of immunoreactive insulin was performed in all participants, and the levels of peroxiredoxin 4 were measured using ELISA method. RESULTS: We found significantly higher levels of peroxiredoxin 4 in patients with prediabetes compared to controls (2851·2 ± 4576·6 pg/ml vs 1088·0 ± 753·3 pg/ml; P = 0·022). There was a mild but statistically significant correlation between peroxiredoxin 4 and weight (r = 0·232; P = 0·038), waist circumference (r = 0·239; P = 0·044), creatinine (r = 0·264; P = 0·019), liver enzymes (ASAT - r = 0·289; P = 0·019 and ALAT - r = 0·305; P = 0·07) and white blood cells count (r = 0·317; P = 0·005). There was no difference in peroxiredoxin 4 levels in patients with and without insulin resistance, as well as with and without metabolic syndrome (MetS), although the levels of peroxiredoxin 4 increased with the number of components of MetS. CONCLUSIONS: The levels of peroxiredoxin 4 are higher in patients with prediabetes, but are similar in subjects with and without insulin resistance, which suggests that the main factor for its increased levels is hyperglycaemia and not insulin sensitivity state.

Serum Proteomics Analysis in Rats of Immunosuppression Induced by Chronic Stress.

The immune system can be damaged by chronic stress. However, for this process, the involved molecular alterations and their regulatory roles played in immunosuppression still remain unclear. This study was aimed to identify the differences in serum protein expressions that are closely associated with the effect of chronic stress on immune function. Serum protein levels of rats in control group and chronic stress group were measured by iTRAQ analysis. Subsequently, among the 121 differentially expressed proteins screened between the two groups, 46 proteins were upregulated (>1.5-fold, P < 0.05), while 75 proteins were downregulated (<0.67-fold, P < 0.05). Bioinformatics analysis revealed that most of the differentially expressed proteins were in relation with the metabolic, cellular, response stimulus and immune system processes. The significantly differential expression of ceruloplasmin, haptoglobin, catalase and peroxiredoxin-1 were picked out for reconfirmation by ELISA analysis. The results were consistent with those obtained by iTRAQ. What is more, the roles of above-mentioned four proteins, apolipoprotein B-100 and heat-shock protein 90 in immunosuppression induced by chronic stress were discussed. Taken together, these findings may provide a new insight into better understanding the molecular mechanisms of immunosuppression induced by chronic stress.

Cysteine Oxidation Targets Peroxiredoxins 1 and 2 for Exosomal Release through a Novel Mechanism of Redox-Dependent Secretion.

Nonclassical protein secretion is of major importance as a number of cytokines and inflammatory mediators are secreted via this route. Current evidence indicates that there are several mechanistically distinct methods of nonclassical secretion. We have shown recently that peroxiredoxin (Prdx) 1 and Prdx2 are released by various cells upon exposure to inflammatory stimuli such as lipopolysaccharide (LPS) or tumor necrosis factor alpha (TNF-α). The released Prdx then acts to induce production of inflammatory cytokines. However, Prdx1 and 2 do not have signal peptides and therefore must be secreted by alternative mechanisms, as has been postulated for the inflammatory mediators interleukin-1ß (IL-1ß) and high mobility group box-1 (HMGB1). We show here that circulating Prdx1 and 2 are present exclusively as disulfide-linked homodimers. Inflammatory stimuli also induce in vitro release of Prdx1 and 2 as disulfide-linked homodimers. Mutation of cysteines Cys51 or Cys172 (but not Cys70) in Prdx2, and Cys52 or Cys173 (but not Cys71 or Cys83) in Prdx1 prevented dimer formation and this was associated with inhibition of their TNF-α-induced release. Thus, the presence and oxidation of key cysteine residues in these proteins are a prerequisite for their secretion in response to TNF-α, and this release can be induced with an oxidant. By contrast, the secretion of the nuclear-associated danger signal HMGB1 is independent of cysteine oxidation, as shown by experiments with a cysteine-free HMGB1 mutant. Release of Prdx1 and 2 is not prevented by inhibitors of the classical secretory pathway, instead, both Prdx1 and 2 are released in exosomes from both human embryonic kidney (HEK) cells and monocytic cells. Serum Prdx1 and 2 also are associated with the exosomes. These results describe a novel pathway of protein secretion mediated by cysteine oxidation that underlines the importance of redox-dependent signaling mechanisms in inflammation.

Accumulation of oxidized peroxiredoxin 2 in red blood cells and its prevention.

BACKGROUND: The thiol protein peroxiredoxin 2 (Prx2) is a major red blood cell (RBC) antioxidant that breaks down hydroperoxides and in the process is converted to an oxidized disulfide. Our objective was to determine whether Prx2 becomes oxidized during storage of RBCs, to understand the underlying mechanism, and to find ways of preventing the accumulation of the oxidized form. STUDY DESIGN AND METHODS: RBCs were stored for up to 6 weeks under simulated blood banking conditions and Prx2 oxidation was monitored by nonreducing gel electrophoresis. The ability of the cells to reverse Prx2 oxidation after storage and to respond to added hydrogen peroxide was also evaluated. RESULTS: Prx2 remained predominantly reduced during the first 3 weeks of storage, and then the oxidized form accumulated progressively. In contrast to fresh cells, oxidation was not reversed by incubation with glucose. Storage of RBCs in a high-pH, low-chloride, and high-phosphate/bicarbonate buffer (EAS-76v6) largely prevented accumulation of oxidized Prx for at least 6 weeks, and dihydrolipoic acid (DHLA), but not Rejuvesol, N-acetylcysteine, or α-lipoic acid, was able to reverse or protect against Prx2 oxidation. Additional, Prx2 oxidation occurred when hydrogen peroxide was added. However, this was reversible, suggesting that the reductive capacity was compromised in some but not in all cells. CONCLUSION: Prx2 remains mostly reduced in a high-pH storage solution with buffering capacity. Addition of DHLA to stored RBCs might be advantageous. Prx2 redox status could be used as a biomarker for the quality of stored RBCs.

Improvement of Plasma Biomarkers after Switching Stroke Patients from Other Angiotensin II Type I Receptor Blockers to Olmesartan.

BACKGROUND: Managing hypertension is crucial for preventing stroke recurrence. Some stroke patients experience resistant hypertension. In our experimental stroke model, olmesartan increased the expression of angiotensin (Ang) II converting enzyme-2. We hypothesized that switching to olmesartan affects biomarkers and the blood pressure (BP) in stroke patients whose BP is insufficiently controlled by standard doses of Ang II type I receptor blockers (ARBs) other than olmesartan. METHODS: We recruited 25 patients to study our hypothesis. All had a history of stroke or silent cerebral infarction. We switched them to olmesartan (10-40 mg per day) for 12 weeks and determined their plasma level of Ang-(1-7), peroxiredoxin, oxidized low-density lipoprotein (oxLDL)/ß-2-glycoprotein I (ß2GPI) complex, adiponectin, high mobility group box 1 (HMGB1), and tumor necrosis factor-α (TNFα) and recorded their BP before and after olmesartan treatment. RESULTS: After switching the patients to olmesartan, their plasma level of Ang-(1-7) as a vasoprotective indicator and adiponectin regulating metabolic syndrome was increased, and peroxiredoxin and the oxLDL/ß2GPI complex indicating its antioxidative stress and its proatherogenicity were lower than their baseline. This suggests that olmesartan may be more effective than other ARBs to improve these conditions. Neither HMGB1 nor TNFα reflecting an inflammatory response was affected, suggesting that the anti-inflammatory effects of olmesartan are similar to those of other ARBs. The recommended BP (<140/90) was obtained in 10 of the 25 patients after switching to olmesartan. No adverse events occurred. CONCLUSIONS: Switching from other ARBs to olmesartan may be a promising therapeutic option in patients with resistant hypertension.

Circulating peroxiredoxin 4 and type 2 diabetes risk: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

AIMS/HYPOTHESIS: Oxidative stress plays a key role in the development of type 2 diabetes mellitus. We previously showed that the circulating antioxidant peroxiredoxin 4 (Prx4) is associated with cardiometabolic risk factors. We aimed to evaluate the association of Prx4 with type 2 diabetes risk in the general population. METHODS: We analysed data on 7,972 individuals from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study (49% men, aged 28-75 years) with no diabetes at baseline. Logistic regression models adjusted for age, sex, smoking, waist circumference, hypertension and family history of diabetes were used to estimate the ORs for type 2 diabetes. RESULTS: During a median follow up of 7.7 years, 496 individuals (288 men; 58%) developed type 2 diabetes. The median (Q1-Q3) Prx4 level was 0.84 (0.53-1.40) U/l in individuals who developed type 2 diabetes and 0.68 (0.43-1.08) U/l in individuals who did not develop type 2 diabetes. For every doubling of Prx4 levels, the adjusted OR (95% CI) for type 2 diabetes was 1.16 (1.05-1.29) in the whole population; by sex, it was 1.31 (1.14-1.50) for men and 1.03 (0.87-1.21) for women. Further adjustment for other clinical measures did not materially change the results. The addition of Prx4 to a validated diabetes risk score significantly improved the prediction of type 2 diabetes in men (p = 0.002 for reclassification improvement). CONCLUSIONS/INTERPRETATION: Our findings suggest that elevated serum Prx4 levels are associated with a higher risk of incident type 2 diabetes. For men, taking Prx4 into consideration can improve type 2 diabetes prediction over a validated diabetes risk score; in contrast, there is no improvement in risk prediction for women.

Peroxiredoxin 5 (PRX5) is correlated inversely to systemic markers of inflammation in acute stroke.

BACKGROUND AND PURPOSE: Peroxiredoxins are endogenous antioxidants that function as peroxide and peroxynitrite scavengers. Extracellular peroxiredoxins, however, are shown to initiate inflammation within the ischemic brain through activation of Toll-like receptors. Based on this observation, we hypothesized that plasma peroxiredoxin concentrations in ischemic stroke would correlate biomarkers of inflammation and predict poor outcome. METHODS: In a prospective study of patients with ischemic stroke, plasma peroxiredoxin 5 (PRX5) concentrations and inflammatory biomarkers at day 3 after stroke onset were correlated and the association between PRX5 at day 3 and outcome at 3 months assessed. RESULTS: PRX5 concentrations were available for 98 patients and were lower in those with more severe strokes (P=0.001). PRX5 was inversely correlated to biomarkers of inflammation at day 3 after stroke and did not predict 3-month outcome. CONCLUSIONS: Plasma PRX5 is decreased in severe stoke and inversely correlated to biomarkers of systemic inflammation. These data suggest that PRX5 is not a proinflammatory mediator in acute stroke. Moreover, the inverse relationship between PRX5 and stroke severity suggests that PRX5 is either consumed or its production is impaired in severe stroke. Further study is needed to define the potential role of PRX5 in stroke.

Clusterin expression level correlates with increased oxidative stress in asthmatics.

BACKGROUND: Oxidative stress is thought to play a role in the pathogenesis of asthma. Clusterin is a sensitive cellular biosensor of oxidative stress and has antioxidant properties. The function and expression of clusterin in patients with asthma have not been fully investigated. OBJECTIVE: To investigate whether the expression of clusterin in patients with asthma is regulated by increased oxidative burden and whether clusterin expression could be used to assess the response to inhaled corticosteroids. METHODS: Clusterin levels in serum, induced sputum, and peripheral blood mononuclear cells of patients with asthma were measured by enzyme-linked immunosorbent assay and western blotting and compared with pulmonary function and levels of expression of hyperoxidized peroxiredoxins. Serum concentrations of clusterin in treatment-naive patients were compared before and after inhaled corticosteroid use. RESULTS: Serum clusterin concentration was significantly elevated in patients with severe asthma and was inversely correlated with pulmonary function. The expression of hyperoxidized peroxiredoxins was greatly increased in peripheral blood mononuclear cells of patients with asthma and was strongly correlated with clusterin expression. Serum clusterin concentrations in treatment-naive patients with asthma were decreased significantly after initial treatment with inhaled corticosteroids. CONCLUSION: Clusterin may be a biomarker of asthma severity and the burden of oxidative stress in patients with asthma. Moreover, clusterin may be useful for the prompt assessment of airway inflammation.

CT-proAVP (copeptin), MR-proANP and Peroxiredoxin 4 after cardiac arrest: release profiles and correlation to outcome.

BACKGROUND: Further characterization of the post-cardiac arrest syndrome (PCAS) is essential to better understand the mechanisms resulting in injury and death. We investigated serial serum concentrations of the stress hormone c-terminal provasopressin (CT-proAVP or copeptin), the cardiac biomarker MR-proANP and a biomarker of oxidation injury, Peroxiredoxin 4 (Prx4) in patients treated with mild hypothermia (MHT) after cardiac arrest, and studied their association to the PCAS and long-term outcome. METHODS: Serum samples from cardiac arrest patients were collected serially: at admission, 2, 6, 12, 24, 36, 48 and 72 h after cardiac arrest. CT-proAVP, MR-proANP and Prx4 concentrations were determined and tested for association with two surrogate markers of PCAS (time to return of spontaneous circulation and circulation-SOFA score) and with cerebral performance category (CPC) at 6 months. Good outcome was defined as CPC 1 to 2. RESULTS: Eighty-four patients were included. CT-proAVP, MR-proANP and Prx4 were early biomarkers with maximum concentrations soon after cardiac arrest and with a significant discriminatory ability between good and poor long-term outcome at most time points. CT-proAVP predicted a poor outcome with the highest accuracy, followed by MR-proANP and Prx4 (area under the receiving operating characteristics curve at 12 h of 0.85, 0.77 and 0.76 respectively). CT-proAVP and MR-proANP showed best correlation to the PCAS. CONCLUSION: In 84 resuscitated patients receiving MHT after cardiac arrest, there is a significant difference in concentrations of CT-proAVP, MR-proANP and Prx4 between patients with good and poor outcome. CT-proAVP and MR-proANP have a significant correlation to surrogate markers of the PCAS.

Prognostic role of serum AZGP1, PEDF and PRDX2 in colorectal cancer patients.

This study was designed to develop novel and better reliable serum prognostic biomarkers for colorectal cancer (CRC). A 50 sample set including CRC, adenoma and healthy control sera was used to identify the serum proteins involved in CRC carcinogenesis using serum proteomic approach. Alpha-2-glycoprotein 1, zinc-binding (AZGP1), pigment epithelium derived factor (PEDF) and peroxiredoxin 2 (PRDX2) were selected as good candidates. Two independent cohorts of 868 individuals were enrolled. The expression of selected proteins in serum from cohort 1 (n = 534) was quantified with enzyme-linked immunosorbent assays. CRC sera of this cohort (n = 405) were assigned to training and test sets, which were used to identify and verify the prognostic markers. The prognostic values of identified proteins were further validated in cohort 2 (n = 334) using quantitative reverse transcription PCR and immunohistochemical staining. Our data showed that the elevated AZGP1 and decreased PEDF and PRDX2 expressions in CRC serum and tissues were correlated with liver metastases. In the training set, higher AZGP1 and lower PEDF levels in sera were significantly associated with a poorer overall survival (OS), higher AZGP1 was also associated with a poorer disease-free survival (DFS). This association was verified in the testing set and further validated in patients in cohort 2. Patients with lower PEDF or PRDX2 levels in their CRC tissues had a significantly poorer DFS or OS than patients with high levels of these proteins in cohort 2. Univariate and multivariate analyses indicated that the prognostic performance of serum AZGP1 and PEDF was independent of other clinicopathological factors. We propose that they may serve as prognostic markers and potential therapeutic targets in CRC.

Identification of peroxiredoxin-1 as a novel biomarker of abdominal aortic aneurysm.

OBJECTIVE: In the search of novel biomarkers of abdominal aortic aneurysm (AAA) progression, proteins released by intraluminal thrombus (ILT) were analyzed by a differential proteomic approach. METHODS AND RESULTS: Different layers (luminal/abluminal) of the ILT of AAA were incubated, and the proteins released were analyzed by 2-dimensional difference in-gel electrophoresis. Several differentially expressed proteins involved in main AAA pathological mechanisms (proteolysis, oxidative stress, and thrombosis) were identified by mass spectrometry. Among the proteins identified, peroxiredoxin-1 (PRX-1) was more released by the luminal layer compared with the abluminal layer of the ILT, which was further validated by Western blot, ELISA, and immunohistochemistry. We demonstrated increased PRX-1 serum levels in AAA patients compared with healthy subjects and also positive correlation among PRX-1 and AAA diameter, plasmin-antiplasmin, and myeloperoxidase levels. Finally, a prospective study revealed a positive correlation between PRX-1 serum levels and AAA expansion rate. Moreover, the combination of PRX-1 and AAA size had significantly additive value in predicting growth. CONCLUSIONS: Several proteins associated with AAA pathogenesis have been identified by a proteomic approach in ILT-conditioned medium. Among them, PRX-1 serum levels are increased in AAA patients and correlate with AAA size and growth rate, suggesting the potential use of PRX-1 as a biomarker for AAA evolution.

A novel anti-peroxiredoxin autoantibody in patients with Kawasaki disease.

Antibodies to the anti-oxidative peroxiredoxin (Prx) enzymes occur in both systemic autoimmune disease and vasculitis in adulthood. Because increased oxidative stress induces vasculitis in Kawasaki disease (KD), autoimmunity to Prxs in patients with KD was investigated. The presence of antibodies to Prx 1, 2 and 4 was analyzed by ELISA and Western blot. Of 30 patients with KD, 13 (43.3%) possessed antibodies to Prx 2, whereas these antibodies were present in only 1 of 10 patients (10.0%) with sepsis (4 with purulent meningitis and 6 with septicemia). In contrast, antibodies to Prx 1 and 4 were not detected in either group. There was no significant correlation among the titers of the three antibodies. Clinical parameters were compared between anti-Prx 2-positive and -negative patients. The presence of anti-Prx 2 antibodies correlated with a longer period of fever and poor response to high-dose γ-globulin therapy in patients with KD. Anti-Prx 2-positive patients had significantly greater excretion of urinary 8-isoprostaglandin than did anti-Prx 2-negative patients. These results provide the first evidence for an antibody to Prx 2 in patients with KD. They also suggest that this antibody might serve as a marker of disease severity and be involved in the pathophysiology of vasculitis in some patients with KD.

Ezrin, maspin, peroxiredoxin 2, and heat shock protein 27: potential targets of a streptococcal-induced autoimmune response in psoriasis.

Psoriasis is an HLA-Cw6-associated T cell-mediated autoimmune disease of the skin that is often triggered by streptococcal angina. To identify keratinocyte proteins, which may become psoriatic autoantigens as the result of an immune response against streptococci, rabbits were immunized with heat-killed Streptococcus pyogenes. Streptococcal immunization induced Ab formation against various human keratinocyte proteins. Sera from psoriasis patients reacted against several of these proteins as well. Common serologic reactivities of rabbits and patients included the proteins ezrin, maspin, peroxiredoxin 2 (PRDX2), heat shock protein (hsp)27, and keratin 6. When used for stimulation of blood lymphocytes, ezrin, maspin, PRDX2, and hsp27 induced increased T cell activation in psoriasis patients, which was particularly evident for HLA-Cw6(+) individuals. Ag-specific T cell lines generated with these proteins consisted predominantly of CD8(+) T cells and used TCR beta-chain rearrangements, which were highly homologous to those expanded within the corresponding skin lesion. Several immunodominant epitopes on the different proteins could be defined according to sequence alignments with the whole genome of S. pyogenes. Our data indicate that maspin, ezrin, PRDX2, hsp27, and potentially keratin 6 could act as autoantigens of a streptococcal-induced autoimmune response and represent targets of the exaggerated T cell response in psoriasis. Additionally, ezrin and hsp27 might constitute antigenic links between psoriasis and inflammatory bowel disease, uveitis, or arteriosclerosis, which are clinically associated.

Antioxidant defense system and family environment in adolescents with family history of psychosis.

BACKGROUND: Our objective was to determine antioxidant defence activity in healthy controls (HC) and healthy unaffected second-degree relatives of patients with early onset psychosis (HC-FHP), and to assess its relationship with familiar environment measured using the Family Environment Scale (FES). METHODS: We included 82 HC and 14 HC-FHP aged between 9 and 17 years. Total antioxidant status, lipid peroxidation, antioxidant enzyme activities and glutathione levels were determined in blood samples. RESULTS: There was a significant decrease in the total antioxidant level in the HC-FHP group compared with the HC group (OR = 2.94; p = 0.009), but no between-group differences in the Global Assessment of Functioning (GAF) scale scores. For the FES, the HC-FHP group had significantly higher scores in the cohesion (p = 0.007) and intellectual-cultural dimensions (p=0.025). After adjusting for these two FES dimensions, total antioxidant status remained significantly different between groups (OR = 10.86, p = 0.009). CONCLUSIONS: Although causal relationships cannot be assumed, we can state that family environment is not playing a role in inducing oxidative stress in these healthy subjects. It could be hypothesized that families with affected relatives protect themselves from psychosis with positive environmental factors such as cohesion and intellectual-cultural activities.