In silico investigation of the interactions of certain drugs proposed for the treatment of Covid-19 with the paraoxonase-1.

Coronavirus disease 2019 (Covid-19) has caused one of the biggest pandemics of modern times, infected over 240 million people and killed over 4.9 million people, and continues to do so. Although many drugs are widely recommended in the treatment of this disease, the interactions of these drugs with an anti-atherosclerotic enzyme, paraoxonase-1 (PON1), are not well known. In our study, we investigated the interactions of 18 different drugs, which are claimed to be effective against covid-19, with the PON1 enzyme and its genetics variants L55M and Q192R with molecular docking, molecular dynamics simulation and free energy calculation method MM/PBSA. We found that ruxolitinib, dexamethasone, colchicine; dexamethasone, sitagliptin, baricitinib and galidesivir, ruxolitinib, hydroxychloroquine were the most effective compounds in binding PON1-w, PON1L55M and PON1Q192R respectively. Mainly, sitagliptin, galidesivir and hydroxychloroquine have attracted attention by showing very high affinity (<-300 kJ/mol) according to the MM/PBSA method. We concluded that the drug interactions should be considered and more attention should be paid in the use of these drugs.Communicated by Ramaswamy H. Sarma.

Evaluation of circulating miR-122, miR-30c and miR-33a levels and their association with lipids, lipoproteins in postprandial lipemia.

AIMS: Postprandial lipemia is characterized by an increase in triglyceride-rich lipoproteins after fatty meals. MicroRNAs (miRs) play important roles in lipid and lipoprotein metabolism. The aim of this study was to determine relationship between levels of plasma miR expression and lipoprotein metabolism-related proteins in subjects with normal (NPR) and high postprandial response (HPR) in postprandial period. MATERIALS AND METHODS: The oral fat tolerance test was applied to 22 individuals with NPR and 22 with HPR. KEY FINDINGS: Increased expressions of miR-122 and miR-33a and miR-122/30c ratio and decreased miR-30c expression were observed in fasting and postprandial period of HPR compared with NPR. ROC curve analysis showed that miR-122/30c ratio is a good biomarker for postprandial lipemia (AUC: 0.97, p < 0.001). Levels of TG, MTTP, and Apo B-48 and chylomicron (CM) particle size were significantly higher in HPR than in NPR (p < 0.05). The miR-122/30c ratio at 2 h was positively correlated with CM particle size, and with TG, MTTP and Apo B-48 levels at 4th hour. miR-33a expression decreased in HPR and was negatively correlated with ABCA1 and Apo A-1 levels at 4th hour of the postprandial period in both groups. SIGNIFICANCE: Increased miR-122 and decreased miR-30c expression levels in HPR may play critical roles in elevated or prolonged postprandial lipemia. The miR122/30c ratio exhibited good association with MTTP, Apo B-48 and TG levels, and with CM particle size, and may be a reliable marker for evaluating postprandial lipemia. miR-33a may also play a key role in decreased HDL-C in postprandial lipemia.

l-theanine alleviates liver and kidney dysfunction in septic rats induced by cecal ligation and puncture.

AIMS: Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response against infection that triggers systemic inflammatory response syndrome. l-theanine (LT), a glutamate derivative, is a non-protein amino acid derived from tea (Camellia sinensis), and a valuable nutraceutical product used as an additive in the food industry. This study we aimed to investigate whether LT would exert any therapeutic effect on liver and kidney tissues in Sprague Dawley rats with sepsis induced with cecal ligation and puncture (CLP). MAIN METHODS: Rats were divided into four groups; sham, CLP, CLP+LT1 (2x250 mg/kg) and CLP+LT2 (2 × 750 mg/kg). Liver and kidney tissues were subjected to histopathological examination. Apoptotic index percentages (AI%) were examined using the TUNEL method. The oxidized glutathione to total glutathione (GSSG/TGSH) ratio (as a marker of oxidative stress, levels of caspase-3 (a marker of apoptosis), glutathione peroxidase (GPx) and glutathione S-transferase (GST) (as antioxidant enzymes), inducible nitric oxide synthase (iNOS) and the tumor necrosis factor-α to Interleukin-10 ratio (TNF-α/IL-10) (as markers of inflammation) were investigated using commercial kits. Levels of malondialdehyde (MDA) (a marker of oxidative stress) were determined spectrophotometrically. KEY FINDINGS: A high dose of LT exhibited more significant effects in reducing oxidative stress, inflammation and apoptosis than a low dose of LT in liver and kidney tissues with CLP-induced sepsis (p < 0.05). SIGNIFICANCE: Our results indicated that LT significantly and dose-dependently inhibited sepsis induced liver and kidney injury. This effect may be attributed to the antioxidant, anti-inflammatory, and anti-apoptotic activities of LT.

Ethyl pyruvate treatment ameliorates pancreatic damage: evidence from a rat model of acute necrotizing pancreatitis.

INTRODUCTION: Ethyl pyruvate (EP), a natural flavoring and fragrance agent, has been shown to exert anti-inflammatory and antioxidant actions. We tested the potential beneficial effects of EP in a rat model of acute necrotizing pancreatitis (ANP), a serious condition with a significant inflammatory explosion and oxidative stress. MATERIAL AND METHODS: Fifty-two adult male Sprague-Dawley rats were divided into four groups: sham + saline, sham + EP, ANP + saline, and ANP + EP. The ANP was induced by glycodeoxycholic acid and cerulein. Animals were sacrificed at 48 h and biochemical, hematological, and histological markers of ANP and inflammation were assessed. The extent of mortality, systemic cardiorespiratory variables, pancreatic microcirculation, renal/hepatic functions, acinar cell injury and enzyme markers for pancreas and lung tissues were investigated. RESULTS: The EP-treated ANP group presented significantly lower mortality than the untreated ANP group (44% (7/16) vs. 19% (3/16), respectively, p < 0.05). Administration of EP resulted in significantly lower levels of IL-6 (ANP + saline: 5470 ±280 vs. ANP + EP: 2250 ±180 pg/ml, p < 0.05). Compared with the ANP group, the ANP + EP group had a lower pancreatic necrosis score (1.45 ±0.2 vs. 0.96 ±0.2, p < 0.05). Moreover, intraperitoneal EP administration had a positive effect on most indices of pancreatitis (amylase and alanine transaminase levels) and lung damage (except lung malondialdehyde levels) as they decreased towards baseline values. CONCLUSIONS: The results from this experimental study indicate that EP, a nontoxic chemical approved by the Food and Drug Administration as a food additive, provides positive effects on the course of pancreatitis, suggesting potential usefulness in management of ANP.

Relationship between postprandial lipemia and atherogenic factors in healthy subjects by considering gender differences.

BACKGROUND: Postprandial triglyceride concentrations are clinically significant and independent predictor of cardiovascular disease risk. The purpose of this study was to determine postprandial TG ranges in healthy subjects by considering gender differences. Secondly, assess the relationship between postprandial lipemia and atherogenic indicators. Finally, investigate the use of the postprandial 4h TG test instead of the area under the curve (AUC). METHODS: Postprandial lipemia was investigated using the standardized oral fat tolerance test (OFTT) in 96 healthy subjects (45 female/51 male). Study group was categorized into tertiles based on AUC calculated using TG concentrations at fasting and 2, 4 and 6h after OFTT. Lipid, lipoproteins, apolipoproteins, LDL subfractions and oxidized LDL (oxLDL) were evaluated in tertiles in both sex groups. RESULTS: The cut-off concentrations for postprandial 4-hour TG concentrations in female and male were 3.20 mmol/L and 4.59 mmol/L, respectively. We observed higher concentrations for atherogenic indicates like small dense-low density lipoprotein (sdLDL), oxLDL values in top tertiles for both groups (P < 0.05). Cohen's kappa coefficients for the agreement of AUC and 4h postprandial TG tests were 0.935, 0.970, 0.469 (P = 0.0001) in female, male and total study group, respectively. CONCLUSION: Due to predominant effects of gender differences on postprandial lipemia, postprandial TG cut-off values for female and male subjects should be determined separately. Postprandial lipemia may be associated with atherogenic tendency by changing lipids, lipoproteins, sdLDL and oxLDL concentrations, especially in males. Four-hour postprandial TG concentrations emerged as a useful and reliable marker for evaluation of postprandial lipemia.

N-acetylcysteine amid reduces pancreatic damage in a rat model of acute necrotizing pancreatitis.

BACKGROUND: Inflammatory explosion and oxidative stress are important mechanisms of injury in acute necrotizing pancreatitis (ANP). This study investigated the effects of N-acetylcysteine amid (NACA), a novel cell-permeant antioxidant with anti-inflammatory activity, on experimental ANP in rats. MATERIALS AND METHODS: Fifty-two adult male Sprague-Dawley rats were used, and ANP was induced by cerulein. The animals were divided into four groups which were sham + saline, sham + NACA, ANP + saline, and ANP + NACA. NACA (2.2 mg/kg, i.p) was administered for 6 h, after the induction of ANP. The extent of acinar cell injury, mortality, systemic cardiorespiratory variables, functional capillary density, renal/hepatic functions, and changes in some enzyme markers for pancreas and lung tissues were investigated. RESULTS: Induction of ANP increased mortality from 0% in the sham group to 43.75% in the ANP + saline group (P < 0.05), and administration of NACA significantly reduced mortality to 12.5% (P < 0.05). Induction of ANP also caused increases in pancreatic necrosis, serum amylase, alanine aminotransferase (ALT), interleukin-6, LDH in bronchoalveolar lavage fluid, serum urea, tissue myeloperoxidase in pancreas and lung tissues and malondialdehyde. There was less pronounced increase in these parameters in NACA treated group. Compared with ANP group, ANP + NACA group had lower levels of pancreatic necrosis (0.5 ± 0.2 versus 1.45 ± 0.2, P < 0.05) and inflammation (0.6 ± 0.2 versus 1.29 ± 00.3, P < 0.05) scores. CONCLUSIONS: Administration of NACA significantly decreased the ANP-induced mortality and also provided significant improvements in hemodynamic changes. The obtained positive effects of NACA on the course of pancreatitis indicates its potential usefulness in the management of ANP.

Effects of glutamine alone on the acute necrotizing pancreatitis in rats.

BACKGROUND: The effects of the glutamine on the acute pancreatitis are controversial in the clinical and experimental studies. The aim of this study was to investigate the influence of glutamine alone on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. MATERIAL AND METHODS: Fifty-two male Sprague-Dawley rats weighing 300-350 g were used. Rats were divided into four groups as sham + saline, sham + glutamine, ANP + saline and ANP + glutamine. ANP in rats was induced by glycodeoxycholic acid. The extent of acinar cell injury, mortality, systemic cardiorespiratory variables, functional capillary density, renal/hepatic functions, and changes in some enzyme markers for pancreatic and lung tissue were investigated during ANP in rats. RESULTS: The induction of ANP resulted in a significant increase in the mortality rate, pancreatic necrosis, and serum activity of amylase, alanine aminotransferase, interleukin-6, lactate dehydrogenase in bronchoalveolar lavage fluid, serum concentration of urea, and tissue activity of myeloperoxidase and malondialdehyde in the pancreas and lung, and a significant decrease in concentrations of calcium, blood pressure, urine output, pO2, and functional capillary density. The use of glutamine alone improved these changes. CONCLUSIONS: Glutamine demonstrated beneficial effect on the course of ANP in rats. Therefore, it may be used by itself in the treatment of acute pancreatitis.

The role of adipocytokines on depressive symptoms of patients with chronic kidney disease.

OBJECTIVE: The aim of this study is to evaluate depression and anxiety scores among chronic kidney disease (CKD) patients and to search the changes of serum concentrations of adipokines with respect to emotional disturbances of CKD patients. PATIENTS AND METHODS: 150 patients recruited into this cross-sectional analytic study. Study groups were control, hemodialysis, predialysis, peritoneal dialysis and kidney transplantation groups. Fasting morning serum leptin, ghrelin, acylated ghrelin, neuropeptide Y, adiponectin, resistin levels of all of the groups were measured using ELISA (Sandwich) method. A screening interview based on the Structured Clinical Interview for DSM-IV and self-report scales (The Beck Depression [BDI] and The Beck Anxiety Inventory [BAI] and Brief Symptom Inventory [BSI] which is self report scales) were administered and conducted by a trained interviewer. RESULTS: BDI scores were significantly higher in hemodialysis and predialysis groups compared to control group (p = 0.009). Somatization sub scores of BSI were significantly higher in hemodialysis and peritoneal dialysis groups compared to control group (p = 0.041). Also positive symptom distress index scores of BSI were significantly higher in hemodialysis and transplantation groups compared to control group (p = 0.047). BDI score were significantly negatively correlated with duration of education (r = -0.165, p = 0.045), positively correlated with presence of protein energy wasting (r = 0.198, p = 0.016), and resistin levels (r = 0.233, p = 0.004). CONCLUSION: CKD patients had higher BDI, BSI-somatization, BSI-positive symptom distress index scores compared to control group. High serum resistin levels, presence of protein energy wasting might have a role in development of depressive disorders of patients with chronic kidney disease.

Effects of clotrimazol on the acute necrotizing pancreatitis in rats.

This study aims to investigate the influence of clotrimazol (CLTZ) on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. Rats were divided into five groups as sham + saline, sham + CLTZ, sham + polyethylene glycol, ANP + saline, and ANP + CLTZ. ANP in rats was induced by glycodeoxycholic acid. The extent of acinar cell injury, mortality, systemic cardiorespiratory variables, functional capillary density (FCD), renal/hepatic functions, and changes in some enzyme markers for pancreatic and lung tissue were investigated during ANP in rats. The use of CLTZ after the induction of ANP resulted in a significant decrease in the mortality rate, pancreatic necrosis, and serum activity of amylase, alanine aminotransferase, interleukin-6, lactate dehydrogenase in bronchoalveolar lavage fluid, serum concentration of urea, and tissue activity of myeloperoxidase, and malondialdehyde in the pancreas and lung and a significant increase in concentrations of calcium, blood pressure, urine output, pO2, and FCD. This study showed that CLTZ demonstrated beneficial effect on the course of ANP in rats. Therefore, it may be used in the treatment of acute pancreatitis.

Hazelnut-enriched diet improves cardiovascular risk biomarkers beyond a lipid-lowering effect in hypercholesterolemic subjects.

BACKGROUND: Tree nuts, particularly almonds, walnuts, and pistachios, have been shown to possess cardioprotective effects. However, there is little information on the effects of hazelnut consumption on cardiovascular risk markers. METHODS: The antiatherogenic effect of hazelnut before and after consumption in hypercholesterolemic subjects was investigated. Twenty-one hypercholesterolemic volunteers (18 men and 3 women) were recruited in a double control sandwich model intervention study with a single group and three isoenergetic diet periods. These were control diet I (4 weeks), hazelnut-enriched diet (4 weeks; hazelnut contributing 18%-20% of the total daily energy intake), and control diet period II (4 weeks). The cardiovascular risk biomarkers such as endothelial function, using flow-mediated dilation (FMD) technique, low-density lipoprotein (LDL) oxidation products and inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP), soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1 (sVCAM-1) as well as lipids and lipoprotein levels were monitored. RESULTS: Consumption of a hazelnut-enriched diet significantly improved FMD (56.6%), total cholesterol (-7.8%), triacylglycerol (-7.3%), LDL-cholesterol (-6.17%), and high-density lipoprotein cholesterol (6.07%) compared with the control diet I. Oxidized-LDL, hs-CRP, and sVCAM-1 levels were significantly lower in the group ingesting a hazelnut-enriched diet compared with the control diets I and II. Modest correlations between sVCAM-1 and FMD and between sVCAM-1 and hs-CRP were observed (r = -0.49, P < .025; r = 0.66, P < .001, respectively). CONCLUSION: Hazelnut-enriched diets may exert antiatherogenic effect by improving endothelial function, preventing LDL oxidation, and inflammatory markers, in addition to their lipid and lipoprotein-lowering effects. These beneficial effects appeared to be reversible after 4 weeks on a hazelnut-free diet. Therefore, hazelnut may be incorporated into daily diet without change in total caloric intake for sustained health benefit.

Hazelnut consumption decreases the susceptibility of LDL to oxidation, plasma oxidized LDL level and increases the ratio of large/small LDL in normolipidemic healthy subjects.

OBJECTIVE: Nut consumption has beneficial effects on protection for development of atherosclerotic process. METHODS: Single intervention study design was used to determine the effects of hazelnut-enriched diet (1 g/kg/day) during 4 weeks period on atherogenic tendency of low-density lipoprotein (LDL) by evaluating susceptibility of LDL to oxidation, alpha-tocopherol content of LDL, LDL subfractions, plasma oxidized (ox) LDL, lipid and lipoprotein levels in normolipidemic healthy subjects (n=21). Statistical analysis was performed using paired t test, ANOVA for repeated measurements test, Pearson's and Spearman correlation analyses. RESULTS: Lag time for oxidation (baseline 54.6+/- 12.3 min, 15th day 59.3+/- 13.4 min, 30th day 65.2+/- 17.8 min, p=0.001) and ,alpha--tocopherol content of LDL (baseline 4.82+/- 1.2 microg/mg LDL protein, 15th day 4.88+/- 1.4 microg/mg LDL protein, 30th day 5.35+/- 1.7 microg/mg LDL protein, p=0.02) were found to be increased while ox-LDL levels (baseline 57.2+/- 16.2 U/L, 15th day 51.2+/- 13.6 U/L, 30th day 48.2+/- 14.2 U/L, p=0.001) decreased during the study period. Total cholesterol, LDL-cholesterol, apolipoprotein (apo) B and apo B/apo AI ratio were found to be significantly lower while apo AI was higher (p<0.05). In respect to LDL subfraction, ratio of large/small LDL was significantly increased at the end of the study (baseline 3.79+/- 1.35, 15th day 3.41+/- 1.60, 30th day 4.28+/- 2.44, p= 0.046). CONCLUSION: Hazelnut-enriched diet may play important role in decrease in atherogenic tendency of LDL by lowering the susceptibility of LDL to oxidation and plasma ox-LDL levels, and increasing the ratio of large/small LDL beyond its beneficial effect on lipid and lipoprotein levels.

Effects of dual inhibitor of cyclooxygenase and 5-lipoxygenase on acute necrotizing pancreatitis in rats.

BACKGROUND/AIMS: The aim of this study was to investigate the influence of dual inhibitor of cyclooxygenase and 5-lipoxygenase (ER-34122) on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. METHODOLOGY: ANP was induced in 96 rats by standardized intraductal glycodeoxycholic acid infusion and intravenous cerulein infusion. Rats were divided into six groups (6 rats in each group): Sham + saline, sham + ER-34122, which was dissolved in hydroxypropylmetylcellulose (TC-5RW), sham + TC-5RW, ANP + saline, ANP + ER-34122 and ANP + TC-5RW. Six hours after ANP induction ER-34122 (30 mg/kg), saline or TC-5RW was given by feeding tube. At the 12th hour, routine cardio-respirator, renal parameters were monitored to assess organ function. Serum amylase, alanine amino transferase (ALT), interleukin 6 (IL-6), lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, serum concentration of urea, tissue activity of myeloperoxidase (MPO) and malondialdehyde (MDA) in pancreas and lung were measured. Pancreas histology was examined. In the second part of the study 60 rats were studied in four groups similar to first part. Survival of all rats was monitored for 24 hours. RESULTS: The induction of ANP resulted in significant increase in mortality rate, pancreatic necrosis and serum activity of amylase, ALT, IL-6, LDH in BAL fluid, serum concentration of urea, tissue activity of MPO and MDA in pancreas and lung, and significant decrease of serum concentrations of calcium, blood pressure, urine output and pO2. NAC did not change serum activity of amylase. The use of ER-34122 inhibited the changes in blood pressure, pO2, serum activity of ALT, pancreatic MPO and MDA levels, partially urine output, LDH level in BAL fluid and pancreatic damage. But ER-34122 could not effect the changes, such as serum activity of amylase, IL-6, serum concentration of urea and calcium, MPO and MDA levels in lung and the mortality rate. CONCLUSIONS: The use of ER-34122 has a limited value on the course of ANP. It has no role in the treatment of ANP.

The effects of lipid-lowering therapy on paraoxonase activities and their relationships with the oxidant-antioxidant system in patients with dyslipidemia.

BACKGROUND: Atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is used for lipid-lowering therapy, is an effective statin modulating process involved in atherosclerosis. Paraoxonase (PON) associated with high-density lipoprotein (HDL) has been postulated to have a role in protecting low-density lipoprotein (LDL) against oxidative modification. Oxidation of serum LDL is an important early step in the development of atherosclerosis and auto-antibodies against oxidized LDL (AuAb-oxLDL) reflect in-vivo LDL oxidation. DESIGN AND METHODS: To examine the effect of atorvastatin (10 mg/day) therapy on PON activity in serum and HDL, the study group included 40 patients with dyslipidemia (19 women and 21 men), 25 of whom had hypercholesterolemia and of 15 of whom had mixed-type hyperlipidemia. By taking blood samples from the patients, levels of serum lipids, lipid peroxidation product as malondialdehyde (MDA), total antioxidant status (TAS) and AuAb-oxLDL and the activities of PON in serum and isolated HDL were determined. RESULTS: The mean levels of total cholesterol, triglyceride, LDL-cholesterol, MDA and AuAb-oxLDL were decreased while HDL-cholesterol and TAS were increased significantly after lipid-lowering therapy in patients with dyslipidemia. On the other hand, PON activities in serum and HDL were increased significantly. The percentage increase in serum PON activity was associated significantly with the percentage decrease in serum AuAb-oxLDL (r=-0.32, P=0.047) and that of HDL PON activity was associated with the percentage increase in HDL-cholesterol level after atorvastatin therapy (r=0.52, P=0.001). The therapy was more effective in increasing PON activity in patients with HDL levels above 35 mg/dl. CONCLUSION: It was concluded that atorvastatin therapy in dyslipidemic patients decreases the level of oxidative stress and increases PON activity, especially in patients with HDL levels above 35mg/dl.

Effects of the celecoxib on the acute necrotizing pancreatitis in rats.

The investigation of the effects of the celecoxib as a cylooxygenase-2 (COX-2) inhibitor on the course of the acute necrotising pancreatitis (ANP) in rats. ANP was induced in 72 rats by standardized intraductal glycodeoxycholic acid infusion and intravenous cerulein infusion. The rats were divided into four groups (six rats in each group): Sham + saline, sham + celecoxib, ANP + saline, ANP + celecoxib. Six hours later after the ANP induction, celecoxib (10 mg/kg) or saline was given i.p. In the 12th hour, routine cardiorespiratuar, renal parameters were monitored to assess the organ function. The serum amylase, alanine amino transferase (ALT), interleukin 6 (IL-6), lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, the serum concentration of the urea, the tissue activity of myeloperoxidase (MPO) and malondialdehyde (MDA) in pancreas and lungs were measured. The pancreas histology was examined. In the second part of the study, 48 rats were studied in four groups similar to the first part. Survival of all the rats after the induction of ANP was observed for 24 h. The induction of the pancreatitis increased the mortality from 0/12, in the sham groups to 4/12 (30%) in the acute pancreatitis with saline group, 5/12 (42%) in the acute pancreatitis with celecoxib group respectively, heart rate, the serum activities of amylase, ALT, the tissue activities of MPO, MDA in the pancreas and lung, and LDH in BAL fluid, the serum concentration of the urea and IL-6, the degree of the pancreatic damage and decreased the blood pressure, the urine production, pO(2) and the serum concentration of calcium. The use of celecoxib did not alter these changes except the serum IL-6 concentration, urine production and MPO, MDA activities in the tissue of the lungs and pancreas. Serum urea concentration and pancreatic damage in ANP + celecoxib group were insignificantly lesser than ANP + saline group. Whereas treatment with celecoxib improves lung and renal functions, the degree of pancreatic damage partially and the serum IL-6 level completely, it does not improve the cardiovascular and liver functions, the mortality rate and the calcium level. Celecoxib may be useful for the support of some organ functions during ANP in rats.

Effect of plasma from patients with Behçet's disease on the production of nitric oxide in cultured human umbilical vein endothelial cells.

OBJECTIVE: To determine the effect of plasma from patients with Behçet's disease (BD) on the production of nitric oxide (NO) in cultured human umbilical vein endothelial cells (HUVECs). SUBJECTS AND METHODS: NO levels were measured in cell culture media after 24-hour incubation of the cells with plasma obtained from 22 BD patients and 16 age/sex-matched healthy control subjects. After treatment of the patients with colchicine and/or nonsteroidal anti-inflammatory drugs, 12 of the patients were considered to be in the inactive phase of the disease. Levels of NO production were also measured in these 12 patients. In addition to the in vitro experiments, erythrocyte sedimentation rate, alpha(1)-antitrypsin, alpha(2)-macroglobulin and neutrophil counts were measured in the patients and controls. RESULTS: Levels of NO in active state BD patients (15.9 micromol/10(6) cells) were significantly lower than values obtained from both patients in the inactive period (19.2 micromol/10(6) cells) and the control group (19.7 micromol/10(6) cells). No significant differences were observed in induced NO products between the patients in the inactive stage and control subjects. CONCLUSION: Plasma from BD patients decreased the level of NO production in the HUVECs, and therefore may cause dysfunction in the endothelial NO synthase activity.

The effects of lipid-lowering therapy on low-density lipoprotein auto-antibodies: relationship with low-density lipoprotein oxidation and plasma total antioxidant status.

BACKGROUND: Oxidized low-density lipoprotein (Ox-LDL) is believed to play an important role in the progression of atherosclerosis. Oxidative modification of low-density lipoprotein (LDL) is a prerequisite for rapid accumulation of LDL in macrophages and for the formation of foam cells. Because of high antioxidant levels in plasma, LDL oxidation is suggested to occur mainly in the subendothelial space of the arterial wall, where there is the concomitant presence of large amounts of reactive oxygen species generated by endothelial cells and activated leukocytes. After Ox-LDL formation, antibodies against this form of LDL may occur. Auto-antibodies against Ox-LDL (AuAb-Ox-LDL) show directly in in-vivo LDL oxidation. Many studies have indicated that the amount of antibodies in serum is positively correlated to the rate of progression of atherosclerotic plaques. DESIGN AND METHODS: In this study the effect of lipid-lowering therapy on the levels of AuAb-Ox-LDL in patients with dyslipidemia was determined using atorvastatin (10 mg/day), and the relationship between the antibodies and plasma total antioxidant status (TAS) and LDL oxidation capacity was also investigated. Serum levels of AuAb-Ox-LDL, lipids, lipoproteins, TAS and susceptibility of LDL to oxidation were determined using lag time in 44 patients with dyslipidemia (29 with hypercholesterolemia and 15 with mixed-type hyperlipidemia). RESULTS: After lipid-lowering therapy, serum levels of AuAb-Ox-LDL were found to be significantly decreased, by 18.7%, while lag time and plasma TAS were increased (31.3% and 7.6% respectively) in patients with dyslipidemia. The percentage change in lag time was found to be negatively correlated to the percentage change in AuAb-Ox-LDL (r = -0.31, P < 0.05). The percentage change in lag time also showed a positive correlation with the percentage change in TAS (r = 0.58, P < 0.01). AuAb-Ox-LDL levels decreased by 21.7% in patients with hypercholesterolemia and by 12.6% in patients with mixed-type hyperlipidemia. Also AuAb-Ox-LDL levels in patients with hypercholesterolemia were higher than in those with mixed-type hyperlipidemia (367 +/- 294 compared with 300 +/- 176 mU/l). CONCLUSION: It was concluded that lipid-lowering therapy may contribute to the reduction in levels of AuAb-Ox-LDL and the increase in the antioxidant capacity of plasma LDL and TAS. It was also suggested that the measurement of antibodies against Ox-LDL during lipid-lowering therapy may be used as an important marker for representing in-vivo LDL oxidation and atherosclerotic processes.