Serum Levels of PCSK9 Are Increased in Patients With Active Ulcerative Colitis Representing a Potential Biomarker of Disease Activity: A Cross-sectional Study.

BACKGROUND/GOAL: Ulcerative colitis (UC) is characterized by chronic inflammation and progressive course, with potential extraintestinal complications including cardiovascular mortality. Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels have been recently recognized as biomarkers of low-grade inflammation and cardiovascular disease. The aim of our study was to evaluate PCSK9 levels in patients with UC and different degrees of disease activity. METHODS: We prospectively recruited consecutive patients with UC attending our center at the University Hospital of Padua. Demographics, clinical characteristics, and biochemical data, including PCSK9, high sensitivity C-reactive protein, and fecal calprotectin, were recorded. Moreover, endoscopic procedures were performed in all subjects. RESULTS: We included 112 patients with UC (mean age=52.62±12.84 y; 52.62% males). Patients with UC and abnormal fecal calprotectin (≥250 µg/g) and/or C-reactive protein (≥3 mg/L) had greater levels of PCSK9 compared with UC patients with normal fecal calprotectin and high sensitivity C-reactive protein ( P =0.03 and 0.005, respectively). Higher endoscopic scores in UC were characterized by greater levels of PCSK9 ( P =0.03). Furthermore, we found a positive correlation between PCSK9 levels and fecal calprotectin ( r =0.18, P =0.04), endoscopic Mayo Score ( r =0.25, P =0.007), and UC-Riley Index ( r =0.22, P =0.01). We also found a positive correlation between PCSK9 levels and both total and low-density lipoprotein cholesterol values ( P <0.05). CONCLUSIONS: Serum PCSK9 levels are increased in patients with biochemical and endoscopic evidence of active disease in UC. Further longitudinal studies are necessary to evaluate the role of PCSK9 as a potential biomarker of disease activity and cardiovascular risk in UC.

Effects of Croton lechleri sap (Sangre de Drago) on AGEs formation, LDL oxidation and oxidative stress related to vascular diseases.

The sap of Croton lechleri Müll. Arg. (Euphorbiaceae) is well-known in South American traditional medicine. This research investigated its activity against glycation and oxidative stress (glycoxidation) to estimate its usefulness in ROS-related diseases. The activity of the sap on albumin glycation, LDL oxidation and ROS formation was detected. C. lechleri sap inhibited BSA glycation and exhibited a protective effect against LDL oxidation; at the concentration of 0.8 µg/mL, it extended the Lag phase of almost 60%. Furthermore, the sap was studied on cell viability and ROS production in HUVEC showing valuable free-radical scavenging activity. In detail, the sap (1.0 and 10.0 µg/mL) significantly decreased the baseline level and H2O2-induced ROS production in HUVEC. This research showed for the first time the ability of C. lechleri sap to decrease the albumin glycation, LDL oxidation and ROS formation in HUVEC, supporting its potential in vascular diseases.

Long-term effect of pioglitazone vs glimepiride on lipoprotein oxidation in patients with type 2 diabetes: a prospective randomized study.

AIMS: Type 2 diabetes (DM2) is associated to oxidative modifications of high-density lipoproteins (HDL), which can interfere with their function. Pioglitazone has proved effective in raising HDL cholesterol (HDL-C) and lowering small dense low-density lipoprotein (LDL), but no clinical studies have examined its effect on lipoprotein oxidation in patients with DM2. METHODS: We assessed the effect of pioglitazone vs glimepiride after 1 year on HDL oxidation, expressed as relative abundance of peptides containing Met112O in ApoA-I (oxApoA-I) estimated by mass spectrometry (MALDI/TOF/TOF), in 95 patients with DM2. The oxLDL and AGE were quantified by ELISA. RESULTS: Patients receiving pioglitazone showed a significant increase in the concentration of ApoA-I (Δ = 7.2 ± 14.8 mg/dL, p < 0.02) and a reduction in oxApoA-I (Δ = - 1.0 ± 2.6%, p < 0.02); this reduction was not significantly different from glimepiride. oxLDL showed a slight, but not significant increase in both treatment groups. Regression analysis showed a correlation between ΔoxApoA-I and ΔAGE (r = 0.30; p = 0.007) in all patients, while both of these parameters were unrelated to changes in HbA1c, HDL-C, duration of illness, or use of statins. CONCLUSIONS: Long-term treatment with pioglitazone was effective in reducing the oxidation of HDL, but not LDL in patients with DM2, while glimepiride didn't. This finding seems to be associated to the change of glyco-oxidation status, not to any improvement in glycemic control or lipid profile. TRIAL REGISTRATION: NCT00700856, ClinicalTrials.gov Registered June 18, 2008.

Activity of myricetin and other plant-derived polyhydroxyl compounds in human LDL and human vascular endothelial cells against oxidative stress.

Studies indicate that oxidative modifications of endothelium and LDL play a preeminent role in atherogenesis; therefore, the preservation of the endothelial antioxidant capacity and the inhibition of LDL oxidation by use of plant-derived compounds are an appealing strategy against several vascular disorders. On this basis, baicalein, eupatorin, galangin, magnolol, myricetin, oleuropein, silibinin and bilobalide were studied against various oxidative conditions. The radical scavenging capacity was analysed using DPPH and ORAC assays. Furthermore, the LDL oxidation was detected by measuring the formation of thiobarbituric acid reactive substances (TBARS) and by monitoring the oxidation kinetics. Further, we used cultured HUVEC to investigate the activities of the polyhydroxyl compounds towards the oxidative stress induced by H2O2. The lowest levels of TBARS were observed in the presence of oleuropein and baicalein, while myricetin, magnolol and eupatorin inhibited these ones to a lesser extent. In addition, oleuropein and myricetin exhibited higher protection in copper-induced LDL oxidation kinetics. However, only myricetin and galangin showed significant protective effects against H2O2 oxidative injury in HUVEC cells. Taken all together the results indicate myricetin as the most active agent among the selected plant-derived polyhydroxyl compounds, with prominent capacities against ox-LDL and ROS production in HUVEC.

An effective and rapid determination by MALDI/TOF/TOF of methionine sulphoxide content of ApoA-I in type 2 diabetic patients.

Increased oxidation of low density lipoprotein (LDL) is characteristic of atherosclerosis. In this frame, high density lipoproteins (HDL) play an important role, being able to remove lipid peroxides (LPOs) and cholesterol from oxidized LDL, so exhibiting a protective role against atherosclerosis. A wide range of reactive compounds lead to the oxidation of methionine (Met) residues with the formation of methionine sulphoxide (MetO) in apolipoprotein A-I (ApoA-I). Consequently, the determination of MetO level can give both an evaluation of oxidative stress and the reduced capability of ApoA-I in LPOs and cholesterol transport. For these reasons, the development of analytical methods able to determine the MetO level is surely of interest, and we report here the results obtained by MALDI mass spectrometry.

Subclinical diastolic dysfunction in type 2 diabetic patients with and without carotid atherosclerosis: relationship with glyco-oxidation, lipid-oxidation and antioxidant status.

OBJECTIVES: The aim of this study was to evaluate subclinical diastolic dysfunction in type 2 diabetic patients and its relationship with glyco-oxidation, lipo-oxidation and antioxidant capacity in the presence or absence of carotid plaques. BACKGROUND: Subclinical diastolic dysfunction is the early stage of diabetic cardiomyopathy, the pathogenic mechanisms of which are still little known. In particular, few data are available on the role of glyco-oxidation, lipo-oxidation and antioxidant status, factors known to be involved in the atherosclerotic process. METHODS: We assessed myocardial systolic and diastolic functions in 57 consecutive asymptomatic type 2 diabetic patients (24 patients with no carotid plaques; 33 with plaques) and 27 healthy volunteers using transthoracic echocardiography. Glyco-oxidation and lipo-oxidation parameters and antioxidant status were also evaluated in fasting venous blood samples. RESULTS: Systolic function was similar between diabetic patients and controls, while most of the diastolic parameters (A, e', E/A, E/e') differed significantly between diabetics and controls, being worse in the former. Among the diastolic parameters, only the peak late diastolic velocity A differed significantly between the two groups of diabetic patients with no carotid plaques and with plaques (0.72 ± 0.16 m/s vs 0.84 ± 0.25 m/s, p<0.05). The diastolic parameters A and E/e' related to glycemic control, glyco-oxidation and antioxidant capacity, and to LDL size and density. CONCLUSIONS: Glyco-oxidation and antioxidant status, combined with the presence of small, dense LDL correlate with subclinical diastolic dysfunction in type 2 diabetic patients. Atherosclerotic lesions are associated with an altered atrial function.

Low serum truncated-BDNF isoform correlates with higher cognitive impairment in schizophrenia.

Brain-derived neurotrophic factor (BDNF) is a key factor in learning and memory. Altered BDNF-signalling is thought to contribute to the pathogenesis of schizophrenia (SZ) especially in relation to cognitive deficits. However, analysis of serum BDNF as a potential biomarker in schizophrenia has provided controversial data. We hypothesized that these confounding results might be due to a differential regulation of BDNF precursor pro-BDNF (32 KDa) and proteolytic products mature (mat-BDNF; 14 KDa), and truncated-BDNF (28 KDa). Accordingly, we investigated the serum abundance of these BDNF isoforms and its relationship with cognitive impairment in schizophrenia. Schizophrenia was diagnosed with PANSS test. Abbreviated cognitive assessment included tests for attention, perceptual-motor skills, processing speed and memory. Using an ELISA assay, we found a slight reduction in serum BDNF levels in SZ patients (n = 40) with respect to healthy controls (HC, n = 40; p = 0.018). Western-blot analysis revealed increased serum pro-BDNF and mat-BDNF and reduced truncated-BDNF (p < 0.001) in SZ with respect to HC. Patients with an increase in pro-BDNF (n = 15/40) or mat-BDNF (n = 9/40) higher than the HC mean + 2 Standard Deviations (SD) also had >2SD reduction of truncated-BDNF (n = 27/40). Reduced truncated-BDNF correlated significantly with higher positive and lower negative PANNS scores and a worst performance in all cognitive assays but not with antipsychotic type. Measurement of serum truncated-BDNF abundance predicted for high cognitive deficits with sensitivity = 67.5%, specificity = 97.5%, Negative Predictive Value = 75% and Positive Predictive Value = 96.4%. These results suggest deficiency in pro-BDNF processing as a possible biological mechanism underlying schizophrenia with cognitive impairment.

Bariatric surgery improves atherogenic LDL profile by triglyceride reduction.

BACKGROUND: Small dense low-density lipoprotein (LDL) are atherogenic particles frequently observed in obese patients. Fatty acids modulate LDL. Objective of this study was to determine the relations between plasma phospholipid fatty acid composition and the presence of small dense LDL particles in morbidly obese patients treated with laparoscopic gastric banding (LAGB). METHODS: Small dense LDL, plasma lipids, lipoproteins, apoproteins, and phospholipid fatty acid composition (a marker of dietary fatty acid intake) were quantified before and 12 months after surgery in four men and 11 women who were morbidly obese and (BMI > 40 kg/m(2)) eligible for surgery, consecutively treated with LAGB at the Department of Medical and Surgical Sciences of the University of Padova. RESULTS: BMI was 48.3 +/- 4.8 kg/m(2) before and 36.1 +/- 5.5 kg/m(2) after LAGB. Plasma triglycerides and apoprotein E levels significantly decreased, while HDL cholesterol significantly increased after LAGB. A reduction of small dense LDL with an increase of LDL relative flotation (0.34 +/- 0.04 before vs 0.38 +/- 0.03 after LAGB, p < 0.001) was also observed. These modifications were neither related to weight reduction nor to changes in phospholipid fatty acid composition, but they were associated to triglyceride reduction, which explained 76.7% of the LDL relative flotation variation. CONCLUSION: Weight loss obtained by LAGB in morbidly obese subjects was accompanied by triglyceride reduction, high-density lipoprotein increase, and an improvement of the atherogenic LDL profile. Triglyceride reduction, but not the extent of weight loss or dietary fatty acid modifications, is the determinant of modifications of LDL physical properties in these patients.

Lipid and phospholipid profile after bowel resection for Crohn's disease.

BACKGROUND AND AIM: Chronic inflammation, impaired intestinal adsorption, and bowel resection may have an impact on lipid metabolism before and after intestinal surgery for Crohn's disease (CD). The aim of this prospective study was to define the impact of intestinal surgery for CD on plasma phospholipid fatty acid (FA) composition and of serum plasma lipoprotein concentrations and to investigate the role of CD recurrence on lipid parameters. MATERIALS AND METHODS: Twenty-four consecutive patients who had intestinal surgery for CD since December 2004 to March 2006 were enrolled in this prospective study. The total amount of calorie intake and the quality of the aliments, systemic inflammatory activity, and plasma lipoproteins and phospholipid fatty acid composition were determined at operation and at follow-up. Statistical analysis was performed with pair-matched tests. RESULTS: The median follow-up was 6 (4-20) months. During the follow-up, no significant modification of body mass index was observed. An increase of high-density lipoprotein (HDL) cholesterol (p=0.02) without other modifications in the plasma phospholipid FA composition were evidenced after surgery. The comparison between colectomy and ileo-colonic or ileal resection groups did not show any significant difference in the lipoprotein concentration and phospholipid FA profile. The length of resected bowel did not show any significant correlation with any relevant difference in lipid, phospholipid profile, or in inflammatory parameters. Patients who experienced a recurrence of CD reported significantly higher levels of total (p<0.01), HDL (p=0.01), and low-density lipoprotein cholesterol (p=0.01) were observed in patients in remission than in those with recurrent active disease. CONCLUSIONS: Patients who are submitted to intestinal resection for CD improve their inflammatory status as well as their lipid metabolism, and CD recurrence, but not the extent of bowel resection, is the main predictor of alteration of serum lipid concentration.

Metabolic syndrome and cardiovascular disease in the elderly: the Progetto Veneto Anziani (Pro.V.A.) study.

BACKGROUND AND AIMS: The prevalence of the metabolic syndrome increases with age, although only few data are available about its prevalence in the general elderly population. This study describes the prevalence of the metabolic syndrome in an elderly population, and its association with cardiovascular diseases. METHODS: The Progetto Veneto Anziani (Pro.V.A.) is an observational study of 3,099 subjects aged 65 and older, randomly selected from the general population of Northern Italy. Cardiovascular diseases and metabolic syndrome according to Adult Treatment Panel III were evaluated in 2,910 subjects. RESULTS: The metabolic syndrome was present in 25.6% of men and 48.1% of women. Its prevalence was mainly due to high blood pressure (93%) in both sexes, and to abdominal obesity in 73% of women. The prevalence of cardiovascular diseases was significantly higher among subjects with metabolic syndrome. Together with age and former smoking habits, the metabolic syndrome was significantly associated with cardiovascular diseases. High blood pressure and low HDL were independently associated with cardiovascular diseases in men, and with high fasting plasma glucose and waist circumference in women. CONCLUSIONS: The metabolic syndrome is frequent, and significantly but not independently associated with prevalent cardiovascular diseases in the elderly. In old people, rather than the metabolic syndrome per se, some of its components are independently associated with cardiovascular diseases.

Restorative proctocolectomy for ulcerative colitis: impact on lipid metabolism and adipose tissue and serum fatty acids.

The aim of this prospective study was to evaluate the changes of the metabolism of circulating and storage lipids in patients with ulcerative colitis after restorative proctocolectomy. Fifteen consecutive patients and 15 sex- and age-matched healthy controls were enrolled. Disease activity, diet, inflammatory parameters, plasma lipoprotein concentrations, and fatty acids (FA) of serum phospholipids and of the subcutaneous adipose tissue were assessed at colectomy and at ileostomy closure. In ulcerative colitis patients, total cholesterol and docosahexaenoic acid were lower than in healthy subjects (p < 0.01 and p < 0.05). The median interval between colectomy and ileostomy closure was 6 (range 2-9) months. During that interval, the inflammatory parameters improved, high-density lipoproteins (HDL) cholesterol increased (p < 0.01), and low-density (LDL) cholesterol decreased (p = 0.01). At ileostomy closure, serum arachidonic acid levels were increased (p = 0.04), whereas serum oleic acid level was decreased (p = 0.02). In this interval, no significant alteration, either in serum n-3 FA precursors or in the FA of subcutaneous adipose tissue, was observed. The increase of serum arachidonic acid after colectomy might suggest a lower utilization for inflammatory process. The reduction of LDL cholesterol is an index of malabsorption probably due to the accelerated transit and to the exclusion of the terminal ileum caused by the covering ileostomy.

Plasma fatty acids and lipoproteins in type 2 diabetic patients.

BACKGROUND: The dyslipidemia of type 2 diabetic patients is characterized by high VLDL, abnormal LDL composition and low HDL cholesterol concentrations. The aim of this study was to establish whether the type of dietary fats affects LDL size and density and HDL cholesterol concentrations in these patients. METHODS: Plasma phospholipid fatty acid composition, which reflects the type of dietary fatty acids, was quantified by gas chromatography. LDL relative flotation (LDL-Rf), a measure of LDL particle size and density, was determined by single vertical spin density gradient ultracentrifugation in 97 type 2 diabetic patients. RESULTS: By linear regression analysis of the data, plasma fatty acids were associated neither with LDL-cholesterol levels nor with LDL-Rf. The HDL cholesterol concentrations were negatively related with saturated fatty acids (r = -0.23; p = 0.02) but positively related with monounsaturated fatty acids (r = +0.20; p = 0.00). Furthermore, higher HDL concentrations were associated with large and buoyant LDL particles (HDL cholesterol vs LDL-Rf: r = +0.47; p = 0.00). In the multiple regression analysis, the LDL-Rf was significantly related both to triglycerides (beta coefficient = -0.55, p = 0.000) and HDL cholesterol (beta coefficient = 0.19, p = 0.034) concentrations. In a stepwise regression analysis including both triglycerides and HDL cholesterol, triglycerides alone explained the 43.0% of the LDL-Rf variability. CONCLUSIONS: A reduction of the dietary saturated fats and an increment of monounsaturated fats might increase HDL cholesterol concentrations in type 2 diabetic patients. Modifications of LDL composition might be expected from interventions aimed to reduce plasma triglycerides.