Empagliflozin and sacubitril/valsartan reverse methotrexate cardiotoxicity by repressing oxidative stress and hypoxia in heart embryonic H9c2 cardiomyocytes - the role of morphology of mitochondria observed on electron microscopy.

OBJECTIVE: Oxidative stress and hypoxia play an important role in the pathogenesis of various cardiovascular diseases. We aimed to evaluate the effectiveness of sacubitril/valsartan (S/V) and Empagliflozin (EMPA) on hypoxia-inducible factor-1α (HIF-1α) and oxidative stress in H9c2 rat embryonic cardiomyocyte cells. MATERIALS AND METHODS: BH9c2 cardiomyocyte cells were treated with methotrexate (MTX) (10-0.156 µM), empagliflozin (EMPA; 10-0.153 µM) and sacubitril/valsartan (S/V; 100-1.062 µM) for 24, 48 and 72 h. The half maximum inhibitory concentration (IC50) and half maximum excitation concentration (EC50) values of MTX, EMPA and S/V were determined. The cells under investigation were exposed to 2.2 µM MTX before treatment with 2 µM EMPA and 25 µM S/V. The cell viability, lipid peroxidation, oxidation of proteins and antioxidant parameters were measured while morphological changes were also observed by transmission electron microscopy (TEM). RESULTS: The results showed that treatment with 2 µM EMPA, 25 µM S/V or their combination produced a protective effect against the reduction in cell viability caused by 2.2 µM MTX.  While HIF-1α levels plunged to their lowest with S/V treatment, oxidant parameters dipped, and antioxidant parameters soared to their highest level with S/V and EMPA combination treatment. A negative correlation was found between HIF-1α and total antioxidant capacity in the S/V treatment group. CONCLUSIONS: A significant decrease in HIF-1α and oxidant molecules together with an enhancement in antioxidant molecules and normalization of the mitochondria morphology as observed on electron microscopy in S/V and EMPA-treated cells were detected. Although S/V and EMPA have both protective effects against cardiac ischemia and oxidative damage, this effect may be increased more with S/V treatment alone compared to combined treatment.

Ranolazine exhibits anti-inflammatory and antioxidant activities in H9c2 cardiomyocytes.

OBJECTIVE: The aim of this study was to evaluate the effectiveness of ranolazine on hypoxia-inducible factor-1α (HIF-1α) and oxidative stress in H9c2 cardiomyocyte cells. MATERIALS AND METHODS: We have assessed the effects of increasing concentrations of methotrexate (MTX) and ranolazine on proliferation of H9c2 rat cardiomyocyte cells by MTT assay. Malondialdehyde (MDA) protein oxidation [advanced oxidation protein products (AOPPs)], lipid hydroperoxide (LOOH) and xanthine oxidase (XO) activity as oxidative stress markers and HIF-1α levels increased and total thiol (T-SH), catalase (CAT) activity and total antioxidant capacity (TAC) antioxidant capacity markers decreased in MTX-treated cells compared to control cells. RESULTS: Oxidative stress markers decreased, and antioxidant capacity markers increased in cells treated with ranolazine alone compared to control cells. For all parameters, we showed that the levels of oxidant, antioxidant markers and HIF-1α in cells treated with MTX and ranolazine together reached the level of the control group, and ranolazine reversed the oxidative damage caused by MTX. CONCLUSIONS: The cell viability increased the levels of oxidant and prooxidant markers and decreased the levels of antioxidant markers decreased in H9c2 cardiomyocytes induced by oxidative stress. These results suggest that ranolazine may protect the cardiomyocytes from MTX-induced oxidative damage. The effects of ranolazine could result from its antioxidant properties.

CIRCULATING MIR-132, MIR-146A, MIR-222, AND MIR-320 EXPRESSION IN DIFFERENTIAL DIAGNOSIS OF WOMEN WITH POLYCYSTIC OVARY SYNDROME.

Purpose: The aim of the study was to investigate whether the circulating miR-132, miR-146a, miR-222, and miR-320 levels are used in the differential diagnosis of women with polycystic ovary syndrome (PCOS) and healthy women. Methods: This prospective case-control study included 50 women with PCOS and age- and body mass index- matched 50 healthy controls. The hormone and lipid profiles, levels of microRNAs (miRNAs), and parameters of carbohydrate metabolism were measured. Results: Expression levels of miRNAs were assessed using the two-step quantitative real-time polymerase chain reaction. Circulating miR-132, miR-146a and miR-222 levels were significantly downregulated in the PCOS group compared with the control group. The miR-320 levels did not differ between the two groups. Free testosterone was negatively correlated with miR-132, miR-146a and miR-222. Insulin was negatively correlated with miR-132 and miR-146a. Conclusions: The results of the study revealed that miRNA expression, may suggest a possible distinction between healthy women and PCOS patients. miR-132, miR-146a, and miR-222 may have key functions in the pathogenesis of PCOS.

The importance of circulating levels of salusin-α, salusin-ß, and heregulin-ß1 in atherosclerotic coronary arterial disease.

OBJECTIVE: The relationship between the severity of atherosclerotic coronary artery disease (CAD) and circulating levels of salusin-α, salusin-ß and heregulin-ß1 has been investigated. In addition, the relationship with these peptides and high sensitive C-reactive protein (hsCRP) has been investigated. METHODS: The study was conducted on 55 volunteers who had normal coronary angiography (CAG) as the control group, 35 volunteers with the degree of coronary artery stenosis below 50% in CA as the non-critical stenosis group, 37 volunteers with narrowing of one coronary artery above 50% as single vessel group and 41 volunteers with narrowing of more than one coronary artery above 50% as multi-vessel group. One hundred and thirteen volunteers have been included to CAD group. RESULTS: There was no statistically significant difference in serum salusin-α levels between groups. Serum salusin-ß ve hsCRP levels were significantly lower in control group compared to other groups and CAD group. There was no statistically significant difference in salusin-ß and salusin-α levels in reciprocal comparison of other groups other than heregulin-ß1 levels. Heregulin-ß1 levels were significantly lower in 'non-critical occlusion' and 'multiple artery occlusion' groups compared to control group. Heregulin-ß1 levels in 'single artery occlusion' group were significantly higher than control, 'non-critical occlusion' and 'multiple artery occlusion' groups. CONCLUSION: Salusin-α levels does not indicate any significant differences between any groups in our study however the relationship of salusin-α with salusin- ß and heregulin-ß1 levels drives to cogitate that these peptides can be used as biomarkers and therapeutic approaches in CAD. We think that these peptides will be used in laboratories routinely in future in addition to hsCRP for CAD.

Pentraxin-3 levels are associated with vasculitis and disease activity in childhood-onset systemic lupus erythematosus.

Objectives Childhood-onset systemic lupus erythematosus (cSLE) is a multisystemic autoimmune disease characterized by inflammatory organ damage by means of vasculitis. Pentraxin-3 (PTX3) is expressed locally at the sites of inflammatory processes, predominantly from endothelial cells. In adult studies, PTX3 has shown to be an indicator of active vasculitis both in large-vessel and small-vessel vasculitides, as well as in SLE. Moreover, in SLE it has found to be correlated with disease activity, and with some of the clinical manifestations and laboratory parameters. We aimed to ascertain if PTX3 might be a significant mediator in cSLE and if it might indicate active vasculitis during the course of the disease. Methods Serum PTX3 levels were measured in 76 patients with cSLE and 41 healthy subjects. We have investigated its relation with disease activity, damage, clinical features, laboratory parameters and medications. Results Serum levels of PTX3 were found to be increased in cSLE compared to healthy controls (mean ± SD; 10.6 ± 8.2 ng/mL vs 2.7 ± 1.3 ng/mL, p < 0.001). PTX3 concentrations were also in correlation with SLEDAI-2K ( r = 0.57, p < 0.001). When viewed from the clinical perspective, serum PTX3 levels were significantly higher only in patients with active vasculitis ( p < 0.001), Raynaud phenomenon ( p = 0.006) and mucocutaneous manifestations ( p < 0.001). However, an association between PTX3 and age, age at disease onset, disease duration, complement levels, PedSDI score (pediatric version of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index), ESR, CRP, procalcitonin levels, anti-ds DNA antibody, anticardiolipin antibodies was not detected. Conclusions Patients with cSLE have increased levels of serum PTX3 compared to healthy controls. Thus, serum PTX-3 level might be a significant mediator in cSLE. Apart from these, the results support that PTX3 reflects active cutaneous vasculitis in cSLE and correlates with disease activity.

The association of vascular endothelial growth factor, metalloproteinases and their tissue inhibitors with cardiovascular risk factors in the metabolic syndrome.

OBJECTIVE: The present study was proposed to examine the matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) and vascular endothelial growth factor (VEGF) in patients with metabolic syndrome (MetS), and to compare these parameters with healthy controls. We also compared the possible association of the circulating levels of MMP-2, MMP-9, TIMP-1, TIMP-2, and VEGF with cardiovascular risk factors in patients with MetS. We also compared the possible association of the circulating levels of MMP-2, MMP-9, TIMP-1, TIMP-2, and VEGF with cardiovascular risk factors in patients with MetS. PATIENTS AND METHODS: A total of 45 patients with MetS and 17 healthy controls with a body mass index (BMI) less than 25 kg/m2 were enrolled in the study. Plasma MMP-2, MMP-9, TIMP-1, TIMP-2, and VEGF levels were determined using ELISA. RESULTS: TIMP-1,-2, MMP-2,-9 levels were significantly higher in patients with MetS compared with healthy controls (p < 0.001). Carotid intima-media thickness and serum VEGF levels were found to be significantly increased (p < 0.01, p < 0.05 respectively) in MetS compared with healthy controls. According to the ROC curves, TIMP-1 levels were both sensitive (93.3%) and specific (81.2%). CONCLUSIONS: We observed that the patients with MetS have increased circulating concentrations of MMP-9, MMP-2, and TIMP-1, TIMP-2 that are associated with increased concentrations of VEGF. These findings suggest that MMP-2 may have a role in the increased cardiovascular risk of MetS patients.

Comparison of maternal and umbilical cord blood soluble lectin-like oxidized low-density lipoprotein receptor 1 levels in early- and late-onset preeclampsia.

BACKGROUND: The main purpose of this study was to determine the maternal and umbilical cord blood oxidized LDL (oxLDL) and soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) levels in early- and late-onset preeclampsia (PE). MATERIALS AND METHODS: A case-control study was conducted in pregnant women with early-onset (before 34 weeks' gestation n = 19) and late-onset (after 34 weeks' gestation n = 22) PE compared to healthy normotensive pregnant controls (n = 44). Groups were compared for the maternal and umbilical cord plasma oxLDL and serum sLOX-1 levels. RESULTS: The mean maternal and umbilical cord serum sLOX-1 and plasma oxLDL levels were significantly increased in early- and late-onset PE compared to controls (p < 0.001). When early- and late-onset PE women were compared with serum sLOX-1 levels, the increase was more pronounced in early PE (p < 0.001). However, same comparison is not statistically significant in cord blood for oxLDL where as it is significantly higher in maternal blood for oxLDL in early-onset PE group. Maternal and cord blood oxLDL and sLOX-1 levels are positively correlated with each other; however, they are negatively correlated with fetal weight and gestational age. CONCLUSIONS: According to our results, maternal and umbilical cord blood levels of oxLDL and sLOX-1 were higher in preeclamptic pregnant. Thus, for the first time it has been shown that oxLDL and sLOX-1 levels were higher in fetal circulation as well as plasma of preeclamptic pregnant. However, sLOX-1 levels seem to be more implying than oxLDL for the differentiation of early and late preeclampsia.

Changes in oxidative stress parameters and antioxidant status in lung cancer: Western blot analysis of nitrotyrosine and protein carbonyls content.

INTRODUCTION: The source of many diseases, including tumors, lies in an increased generation of reactive oxygen species resulting in oxidative stress. We investigated the relationships between advanced oxidation protein products (AOPPs), nitrotyrosine (NT), protein carbonyls (PCO) content, and the prooxidant-antioxidant balance (PAB) in patients with lung cancer. METHODS: A total of 14 age-matched healthy controls, 14 subjects with non-lung cancer pulmonary disease, and 41 patients with lung cancer were included in this study. Spectrophotometry was used to examine plasma AOPP, serum FRAP, and PAB, while serum PCO and NT were assessed with western blot analysis. RESULTS: A significant difference in AOPP levels were found between patients and controls (p < 0.01). Also, there was a highly significant difference in NT levels between patients and controls (p < 0.001). PAB showed negative correlation with albumin (r = -0.340, p = 0.011) and positive correlation with CRP (r = 0.342, p = 0.011). AOPP, albumin, gender, and smoking were the significant independent variables found by backward stepwise multiple logistic regression (MLR) analysis method. MLR analysis revealed that AOPP was the variable that had a significant effect on lung cancer [(p = 0.006, OR = 1.074, (95% CI) (1.020-1.131)]. CONCLUSIONS: The use of non-invasive diagnostic biochemical parameters would represent a very important contribution to our diagnostic armamentarium in lung cancer, considering the high incidence of this deadly disease. In this regard, AOPP and NT levels have appeared to play a prominent role, although further studies are certainly warranted.

Maternal and cord blood apelin, resistin and visfatin levels in gestational diabetes mellitus.

AIM: The aim of this paper was to investigate maternal and cord blood apelin, resistin and visfatin concentrations in pregnant women with and without gestational diabetes mellitus (GDM). METHODS: This case-control study was conducted on 24 women with GDM and 21 women without GDM. Maternal plasma and cord blood apelin, resistin and visfatin levels were measured with ELISA. RESULTS: The cord blood apelin levels were significantly lower in women with GDM than control subjects (111.23±31.53 vs.. 257.48±133.97 pg/mL, P=0.002). However, the decrease of maternal apelin levels in GDM group was not statistically significant (140.76±48.38 vs. 163.53±91.12 pg/mL, P=0.602). Women with GDM had lower maternal and cord blood visfatin concentrations and higher resistin concentrations than control group. Maternal resistin concentrations were significantly correlated with HOMA-IR (r=0.745, P=0.005). The apelin and visfatin levels did not correlate with HbA1c, BMI, HOMA-IR, glucose and birth weight. CONCLUSION: GDM is associated with lower cord blood apelin levels than control subjects. GDM appears to influence fetoplacental apelin metabolism. Apelin may not be directly involved in the regulation of maternal insulin sensitivity. Our results indicate that there is an increase in resistin concentrations and a decrease in visfatin concentrations in maternal serum and cord blood serum with GDM.

Effects of peritoneal-and hemodialysis on levels of plasma protein and lipid oxidation markers in diabetic patients.

AIM: The aim of this paper was to evaluate the effects of dialysis procedures on oxidative stress in diabetic patients. METHODS: The study was performed on 15 non-diabetic hemodialysis (HD) patients, 30 non-diabetic perinoteal dialysis (PD) patients, 18 diabetic HD patients (DHD), 15 diabetic PD patients (DPD), and 20 healthy controls. Plasma thiobarbituric acid reactive substances (TBARS), protein carbonyl (PCO), and oxidized LDL (oxLDL) were determined as oxidative stress markers. Plasma thiol (P-SH), erythrocyte glutathione (GSH) levels, and serum paraoxonase (PON1) activities were measured as antioxidants. RESULTS: HD patients have significantly higher oxLDL, TBARS and PCO levels and significantly lower P-SH levels than PD patients. DHD patients have significantly higher PCO levels and PON1 activities and significantly lower GSH levels than non-diabetic HD patients. There was no any difference in oxidative stress parameters between DPD and non-diabetic PD patients. CONCLUSION: Oxidative stress is exacerbated by HD in diabetic patients. Treatment strategy with antioxidants in dialysis patients may be associated with a worsened survival.

The role of feed regulating peptides on weight loss in patients with pulmonary tuberculosis.

PURPOSE: Malnutrition is a prominent feature of tuberculosis (TB). The aim of our study was to explore the function of plasma regulatory proteins in pulmonary TB and to investigate the relationship between these parameters and loss of body weight. METHODS: Plasma levels of fasting insulin, leptin, ghrelin, adiponectin and orexin-A were measured in 23 pulmonary TB patients, 39 patients with pulmonary sarcoidosis, 22 patients with different diffuse interstitial lung diseases and 21 healthy patients serving as controls. RESULT: Plasma leptin (p<0.001) and orexin-A (p<0.01) levels were significantly decreased in TB patients compared with those of the other study subjects. TB patients also had higher levels of plasma ghrelin compared with those of the other study subjects, while sarcoidosis patients had higher plasma adiponectin levels than the other study subjects. Glucose levels were similar in all groups, yet, insulin and Homeostasis Model of Assessment-Insulin Resistance (HOMA-IR) levels were significantly higher in the TB group compared to the other study groups. There was no correlation between leptin, ghrelin, adiponectin and orexin-A and other parameters. CONCLUSIONS: These data suggest that leptin and orexin-A levels have effects on weight loss in patients with pulmonary tuberculosis. Particularly, leptin may play a role in the early immune response to pulmonary TB and prolonged inflammation may further suppress leptin production. Measurement of HOMA-IR can indeed be used as a marker for the risk of activated TB. Further clinical studies are needed to better understand the role of feed regulating proteins in pulmonary tuberculosis.

Evaluation of serum paraoxonase and arylesterase activities in subjects with asthma and chronic obstructive lung disease.

BACKGROUND: Asthma and chronic obstructive lung disease (COPD) are characterised by airway inflammation. Paraoxonasel (PON1) and arylesterase (AE) enzymes have the ability to protect HDL from oxidation and may have antiatherogenic, antioxidant, and antiinflammatory features. We carried out a study to assess if there is a difference between PON1 and AE activities and biochemical values between asthmatics and COPD patients and if there is a difference between comorbid or pure COPD patients. METHODS: 40 asthmatics, 20 pure COPD, 20 comorbid COPD patients, and 20 healthy controls were included. We excluded patients with hypertension, metabolic syndrome, diabetes mellitus, thyroid, renal, hepatic, rheumatic, cardiac, cerebrovascular, malignant, and infectious diseases to establish the asthma and pure COPD groups. Patients using drugs which could affect PON1 and AE were excluded in these groups. There were 11 hypertensive, 5 diabetic, and 4 cardiac patients in the comorbid COPD group. PON1 and AE activities were measured spectrophotometrically. RESULTS: Mean age was higher and male gender was more prevalant in COPD than other groups. Fasting blood glucose, LDL-cholesterol, triglyceride, leucocyte counts, erythrocyte sedimentation rate, and hs-CRP levels were higher in COPD patients. Although PON1 and AE were lower in patients than controls, no difference was found between the asthma and COPD groups, nor between pure and comorbid COPD patients. CONCLUSIONS: Although asthma and COPD are two different conditions PON1 and AE activities cannot be markers of differantial diagnosis as they overlap. Comorbid COPD patients may have similar enzyme levels because of the drugs such as statins and aspirin.

Circulating levels of adiponectin, orexin-A, ghrelin and the antioxidant paraoxonase-1 in metabolic syndrome.

AIM: Metabolic syndrome (MS) is a disorder consisting of various abnormalities such as dyslipidemia, obesity, hypertension and hyperglycemia. Over the past two decades, the prevalence of MS has greatly increased, and it has become a global health problem. We measured and compared plasma concentrations of adiponectin, orexin-A, ghrelin and the antioxidant paraoxonase-1 (PON1) between patients with metabolic syndrome (MS) and healthy controls. METHODS: A total of 87 patients (46 women, 41 men) with MS and 40 healthy controls (21 women, 19 men) with a BMI less than 25 kg/m2 were enrolled in the study. The plasma concentrations of the adiponectin, orexin-A, ghrelin and PON1 were measured by ELISA. RESULTS: Plasma concentrations of Orexin-A were significantly higher in patients with MS than controls (P<0.001). However, plasma concentrations of adiponectin, ghrelin and PON1 were significantly lower in patients with MS compared to controls (P<0.001, P<0.001 and P<0.001, respectively). CONCLUSION: Our data confirmed the previous findings that plasma concentrations of orexin-A is higher than controls, however plasma concentrations of PON1, ghrelin and adiponectin are lower compared to controls.

Advanced glycation end products and antioxidant status in nondiabetic and streptozotocin induced diabetic rats: effects of copper treatment.

The effects of Cu(II) supplementation on glycemic parameters, advanced glycation end products (AGEs), antioxidant status (glutathione; GSH and total antioxidant capacity; TAOC) and lipid peroxidative damage (thiobarbituric acid-reactive substances, TBARS) were investigated in streptozotocin (STZ) induced diabetic rats. The study was carried out on Wistar albino rats grouped as control (n = 10), CuCl(2) treated (n = 9), STZ (n = 10) and STZ,CuCl(2) treated (n = 9). STZ was administered intraperitoneally at a single dose of 65 mg/kg and CuCl(2), 4 mg copper/kg, subcutaneously, every 2 days for 60 days. At the end of this period, glucose(mg/dl), Cu(microg/dl), TBARS(micromol/l), TAOC(mmol/l) were measured in plasma, GSH(mg/gHb) in erythrocytes and glycated hemoglobin (GHb)(%) in blood. Plasma AGE-peptides(%) were measured by HPLC flow system with spectrofluorimetric and spectrophotometric detectors connected on-line. Data were analyzed by the non-parametric Kruskal-Wallis and Mann-Whitney U test. In the STZ group glucose, GHb and AGE-peptide levels were all significantly higher than the control group (P < 0.01, P < 0.05, and P < 0.01, respectively). CuCl(2) treated group had significantly lower glucose but significantly higher GHb, TAOC and TBARS levels than the control group (P < 0.05, P < 0.001, P < 0.05 and P < 0.001, respectively). STZ,CuCl(2) treated group had significantly higher GHb, TAOC and TBARS levels compared with the control group (P < 0.001, P < 0.05 and P < 0.05, respectively); but only TAOC level was significantly higher than the STZ group (P < 0.01). This experimental study provides evidence that copper intake increases total antioxidant capacity in both nondiabetic and diabetic states. However despite the potentiated antioxidant defence, lipid peroxidation and glycation enhancing effects of CuCl(2) are evident under nondiabetic conditions.

Hypertension and hemostatic/fibrinolytic balance disorders.

BACKGROUND: Hypertension is one of the principal risk factors for cardiovascular disease. We aimed to evaluate the impact of hypertension on fibrinolytic balance and endothelial function by measuring plasma levels of plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator antigen (tPA), tPA/PAI-1 complex and fibrinogen. METHODS: Patients enrolled into the study were divided into four groups: 22 essential hypertensive (EH), 22 white coat hypertensive (WCH), 22 renovascular hypertensive (RH) and 22 normotensive control subjects. Plasma PAI-1, tPA, tPA/PAI-1 complex levels were measured by enzyme linked immunosorbent assays. RESULTS: There was no difference in the systolic and diastolic blood pressure measurements of the EH and RH groups. The four groups were comparable for age, gender, smoking habits and BMI. Patients with EH, RH and WCH had increased plasma levels of PAI-1, tPA, tPA/PAI-1 complex and fibrinogen compared with controls. No fibrinolytic parameter was associated with blood pressure in hypretensive subjects. CONCLUSION: This prospective study showed that fibrinolytic markers such as PAI-1, tPA, tPA/PAI-1 complex are independently associated with the development of hypertension. This supports the hypothesis that disturbances in fibrinolysis precede a cardiovascular event. Therefore, hypertension may be associated with impaired fibrinolysis.

Potential role of matrix metalloproteinase-2,-9 and tissue inhibitors of metalloproteinase-1,-2 in exudative pleural effusions.

PURPOSE: To investigate diagnostic values of pleural fluid matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitors of metalloproteinase-1 (TIMP-1) and TIMP-2 measurements in tuberculous pleurisy(TP) and malignat pleurisy (MP). METHODS: The study included 24 patients with TP, 22 patients with MP and 15 patients with pleural effusion of non-tuberculous and non-malignant origin as controls. MMP-2,-9 and TIMP-1,-2 levels in pleural fluid were measured by ELISA method. RESULTS: Pleural fluid MMP-2 and MMP-9 levels were higher (P < 0.001, P < 0.001, respectively) in TP than in MP and controls. MP patients have higher pleural fluid MMP-2 and MMP-9 levels (P < 0.01, P < 0.05, respectively) than controls. Pleural fluid TIMP-2 levels were higher (P < 0.01 and P < 0.001, respectively) in MP than in TP and controls. Pleural fluid MMP-9 levels were negatively correlated with pleural fluid TIMP-2 levels (r: 0.464, P=0.029) in patients with MP. CONCLUSIONS: Determination of TIMP-2 in pleural fluid may contribute to differentiate TP from MP. These results suggest that overproduction of MMP-9 and TIMP-2 is associated with accumulation of the pleural effusion in malignancy. Further studies with a greater number of patients are needed to confirm this hypothesis.

Levels of paraoxonase, an index of antioxidant defense, in patients with active sarcoidosis.

OBJECTIVE: Oxidative mechanisms are currently discussed as playing a crucial role in the genesis of inflammatory lung diseases. We aimed to evaluate the oxidant-antioxidant balance in the pathogenesis and activity of sarcoidosis and to search if the change in the level of PON can be taken as an activity marker. METHODS: 26 active sarcoidosis subjects aged 41.3+/-12.9 years, 37 inactive subjects aged 39.6+/-11.7 years and 48 control subjects aged 48.9+/-2.5 years were recruited in our study. Malondialdehyde (MDA), paraoxonase1 (PON1) and oxidized low density lipoprotein (oxLDL) levels in serum were analyzed by spectrophotometric, kinetic, and ELISA methods, respectively. RESULTS: PON1 levels were significantly lower in the active disease state than both the inactive form and control groups. MDA levels were significantly higher in active sarcoidosis than both the inactive disease and control groups, and oxLDL levels were significantly higher in the active disease group than the inactive group and control group. The level of PON1 in the inactive disease group is not significantly different from the control group while the oxLDL and MDA levels of inactive group is significantly higher than the control group (p<0.001). There was a negative correlation between the PON1 activities and MDA values in both active and inactive groups (p=0.008). CONCLUSION: Oxidative stress increases in sarcoidosis might be due to both increase in lipid peroxidation and decrease in antioxidant status (PON1) and the relationship between oxidative status and the activation of the disease should be discussed by comparing the previously known activation criteria.

Influence of propylthiouracil treatment on oxidative stress and nitric oxide in Basedow disease patients.

Oxidative stress parameters and nitric oxide (NO) values were determined in 27 newly diagnosed Basedow patients before and after 1 mo of propylthiouracil (PTU) therapy and in 15 healthy controls. Basedow patients exhibited increased triiodothyronine (T3) and thyroxine (T4) and decreased thyroid-stimulating hormone (TSH) values compared to controls. Significantly higher thiobarbituric acid-reactive substances (TBARS), NO and glutathione (GSH) levels, and CuZn superoxide dismutase (CuZn SOD) activity were found in Basedow patients in comparison to controls, regardless of sex. Treatment with PTU (3 x 100 mg/d for 30 d) was effective in decreasing T1 and T4 and increasing TSH levels. Significantly decreased NO and TBARS and increased GSH and CuZn SOD levels were observed in PTU-treated Basedow patients compared to pre-PTU administration. PTU-treated patients compared to controls still exhibited significantly higher T3 and lower TSH values and higher NO, TBARS, GSH, and CuZn SOD levels. The induced antioxidant defense and decrease in NO) values in response to PTU therapy emphasizes the role of PTU as an antithyroid drug, where the ability to diminish hyperthyroidism results in decreased catabolism and lower oxidant generation.

Secondary venous ischemic injury associated with neutrophil infiltration and lipid peroxidation: amelioration of injury by cyclosporin A in a rat inguinal island flap.

Secondary venous ischemia caused by anastomotic failure is one of the major causes of failure after free tissue transfers and replantations. The effects of cyclosporin A (CsA) on secondary ischemic injury associated with neutrophil infiltration and lipid peroxidation were evaluated in a rat inferior epigastric island skin flap model. Primary ischemia was produced by arteriovenous occlusion for 2 hours. Twenty-four hours later, secondary venous ischemia was produced by 5 hours of venous occlusion. Nonischemic (n = 5), primary ischemic (n = 5), and secondary ischemic control groups (n = 10), and four treatment groups (n = 10) were created. Treatment groups received either 15 or 30 mg per kilogram per day oral CsA for 3 days before flap elevation, or 15 or 30 mg per kilogram intravenous CsA at 4 hours of secondary venous ischemia. Flap survival area, malondialdehyde (MDA) content, and myeloperoxidase (MPO) activity were assayed for each group. The mean flap survival area of the high-dose posttreatment group was significantly higher than the secondary ischemic control group (29% +/- 39% vs. 3% +/- 8%; p < 0.05, Student's t-test). The MDA and MPO levels of each treatment group were significantly lower than the secondary ischemic control group at hours 1 and 24 (p < 0.0001, Student's t-test). The lowest MDA and MPO levels were achieved in the high-dose posttreatment group. Results suggest that CsA may improve flap survival after secondary venous ischemia by attenuating neutrophil infiltration and by reducing lipid peroxidation.