Ferhan Girgin Sagin

Lipids as Key Players in Alzheimer Disease - Alterations in Metabolism and Genetics

Advances in Alzheimer Disease (AD) research suggest that central nervous system (CNS) lipids play a key role in the pathogenesis. This role is attributed to the rich lipid content of CNS structures and the presence of blood brain barrier which disables the exchange of lipids between CNS and plasma. Among these lipids, cholesterol is a unique molecule provided mainly by its de novo synthesis in the CNS. Special apolipoproteins used for its efficient recycling within the CNS and special oxysterols formed that are specific to brain all contribute to the unique properties of the molecule. Above all, the presence of cholesterol in the membrane enables it to function as a regulator of a number of protein related processes such as the beta-amyloid precursor protein cleavage. Cholesterol reducing agents such as statins are recently proposed to have a protective role in AD. This review will focus on the role of cholesterol metabolism and genetics in AD. Current literature investigating the relationship between cholesterol and AD will be evaluated from the pathophysiological perspective. Genetic studies concerning proteins which are involved in the CNS cholesterol metabolism will also be summarized in the hope that genomics may stimulate further studies and thus contribute to a more clear understanding of the molecular mechanisms in the pathophysiology of AD.

SAFETY PROFILES OF Fe2+ AND Fe3+ ORAL PREPARATIONS IN THE TREATMENT OF IRON DEFICIENCY ANEMIA IN CHILDREN

The major purpose of this study was to compare the oxidant-related toxicities of the different oral iron preparations in children with iron deficiency anemia (IDA); the second aim was to investigate the side effects of iron preparations. Seventy-two children with IDA were randomly included in the Fe2+ group (= 39) or the Fe3+ group (= 33). Some oxidizable substrates (erythrocytes malondialdehyde (MDA), urine 8-isoprostane, and basal and Cu-stimulated-oxidized LDL and antioxidant enzyme (superoxide dismutase (SOD), catalase and glutathione peroxidase) activities were evaluated at the beginning and at the 1st, 3rd, and 6th months of therapy. Side effects due to medication were recorded. While at the end of the 1st month SOD levels were significantly increased in Fe3+ group, at the 6th month evaluation, basal-oxidized LDL levels were significantly increased in the Fe3+ group, as was urine 8-isoprostane in the Fe2+ group. No other difference was found between two groups. In conclusion, there were minimal differences between children treated with ferric or ferrous iron in antioxidant system activities, the status of oxidizable substrates, and clinical toxicities.

Oxidative Stress & Antioxidants and PON1 in Health and Disease

Impairment in oxidative stress/antioxidant balance is an important trigger for a variety of diseases. As an antioxidant molecule on high-density lipoprotein (HDL), paraoxonase (PON1) contributes to the antioxidant mechanisms by removing oxidised lipids both on HDL and low-density lipoprotein (LDL). In this chapter, we will document and evaluate the results of our studies on healthy, atheroscleoric and diabetic cases which showed that (a) PON1, superoxide dismutase (SOD) and arylesterase probably work in a collaboration against oxidative stress, especially superoxide radical scavenging; (b) PON1 and SOD activities concomitantly decrease with the oxidative stress & severity of disease (higher HbA1c values in diabetics, more diseased vessels in atherosclerosis) while catalase (CAT) acts the opposite way; (c) Since PON1 activity and erythrocte thiobarbituric acid reactive substances (eTBARS) levels are affected by traditional risk factors (hypertension, aging and gender), determination of arylesterase activity might be a better indicator of antioxidant activity of PON1; (d) SOD activity has the greatest variability in regard to PON1 phenotype therefore it’s important to define the PON1 polymorphism as well as PON1, arylesterase and other antioxidant enzyme activities

Lipoprotein-associated phospholipase A2: a new marker to determine cardiovascular risk in hypercholesterolemic dyslipidaemic children:

Background Inflammation and hypercholesterolaemia contribute to atherosclerotic changes which can start in childhood. Children with hyperlipidaemias are at high risk for early coronary atherosclerosis. This study evaluates the relationship between lipoprotein-associated phospholipase A2 (Lp-PLA2), carotid intima-media thickness (CIMT) and flow-mediated dilatation in hypercholesterolaemic dyslipidaemic children. Methods We performed a case–control study consisting of 43 cases, aged 2 to 17 years, and 24 age-matched controls. Fasting blood samples were obtained from both groups for the measurement of a lipid profile (total cholesterol, LDL-C, HDL-C and triglycerides) and Lp-PLA2 in mass units. The latter was determined with a turbidimetric immunoassay method (PlacTest, DiaDexus Inc.) applied to an automated analyser. CIMT and flow-mediated dilatation measurements were undertaken by a paediatric cardiologist, using high-resolution B-mode ultrasonography. Results Total cholesterol, LDL-C and Lp-PLA2 concentrations were significantly higher in the cases than in the controls (p < 0.001 for all three parameters). While CIMT values were also significantly higher in the patients compared to the controls (P = 0.001), flow-mediated dilatation values were significantly lower (P = 0.001). We found positive correlations between Lp-PLA2 and total cholesterol (r = 0.41, P = 0.001), Lp-PLA2 and LDL-C (r = 0.36, P = 0.004), Lp-PLA2 and CIMT (r = 0.44, P = 0.019) and LDL-C and CIMT (r = 0.41, P = 0.032); there were negative correlations between Lp-PLA2 and flow-mediated dilatation (r = −0.15, P = 0.045), total cholesterol and flow-mediated dilatation (r = −0.45, P = 0.017), LDL-C and flow-mediated dilatation (r = −0.51, P = 0.006) and CIMT and flow-mediated dilatation (r = −0.45, P = 0.016). Conclusion Lp-PLA2 concentrations are significantly elevated in hypercholesterolaemic dyslipidaemic children. Given the association of Lp-PLA2 with markers of atherosclerosis (total cholesterol, LDL-C, CIMT and flow-mediated dilatation), the finding of increased concentrations of Lp-PLA2 could be used to identify early atherosclerotic changes in hypercholesterolaemic dyslipidaemic children and may inform their clinical management.

A panel of oxidative stress assays does not provide supplementary diagnostic information in Behcet's disease patients

BackgroundRecent findings suggest a role of oxidative stress in the pathogenesis of Behcets disease (BD), but the utility of oxidative stress-associated assays in offering diagnostic information or in the monitoring of disease activity is largely unassessed.Objective and methodsWe aimed to measure oxidative and inflammatory markers, along with the markers of reactive nitrogen species, S-nitrosothiols and 3-nitrotyrosine, in BD patients (n = 100) and healthy volunteers (n = 50). These markers were evaluated in regard to their role in the pathogenesis of BD as well as their relation to clinical presentation, disease activity and duration.ResultsMedian values for erythrocyte sedimentation rate (ESR), C-reactive protein, leukocyte count, and IL-18 levels, as well as myeloperoxidase (MPO) activity, were statistically higher in the patient group compared to controls. Some inflammation markers (ESR, neutrophil and leukocyte counts) were statistically higher (p < 0.05) in the active period. In contrast, oxidative stress-associated measures (erythrocyte lipid peroxidation, antioxidant enzymes and measures of serum antioxidant capacity), revealed no statistically significant differences between the median values in BD patients versus healthy control subjects (p > 0.05 in all statistical comparisons), nor was there any difference in median levels of these oxidative stress markers in active disease versus disease remission. S-nitrosothiols and 3-nitrotyrosine were undetectable in BD plasma.ConclusionsThe application of oxidative stress-associated measures to BD blood samples offered no supplemental diagnostic or disease activity information to that provided by standard laboratory measures of inflammation. S-nitrosothiols and 3-nitrotyrosine appeared not to be markers for active BD; thus the search for biochemical markers that will indicate the active period should be continued with larger studies.

Serum Amyloid A and Lipoprotein Associated Phospholipase A2 Levels in Patients with Malign Melanoma: Correlations with Clinical Assessment and Stage

Amaç: Malign melanomlu (MM) hastaların erken tanı ve takibinde kullanılabilecek onaylanmış, sensitif ve spesifik biyobelirteçlerin eksikliği günümüzde önemli sorun teşkil etmektedir. Bu çalışmada yangı ilişkili iki biyobelirteç olan serum amiloid A (SAA) ve lipoprotein ilişkili fosfolipaz A2’nin (Lp-PLA2) melanomun klinik izlemi ve evrelemesindeki korelasyonunu araştırmayı amaçladık. Yöntemler: Histolojik ve klinik olarak doğrulanan MM hastaları (n=131) ve sağlıklı gönüllülerden (n=27) alınan kan örneklerinde laktat dehidrogenaz (LDH) ve C-reaktif protein (CRP) (Routine), SAA ve S100B (ELISA), Lp-PLA2 aktivite düzeyleri (PLAC® Test) çalışılmıştır. Bulgular: MM hastalarında kontrol grubuna kıyasla sedimantasyon düzeyi, LDH, CRP, S100B, SAA ve Lp-PLA2 aktivitesi düzeyleri anlamlı olarak daha yüksek bulunmuştur (p<0,05). Hastalık evresiyle en güçlü korelasyon gösteren belirteç SAA olarak saptanmıştır (Spearman’s korelasyon analizinde rho katsayısı 0,622, p=0,000). İşlem karakteristik değerlendirmelerine göre en geniş eğri altında kalan alanı gösteren=0,984, p=0,000, en yüksek sensitivite (%95) ve spesifite (%93) SAA’da saptanmıştır. Pearson testi sonuçlarına göre SAA düzeyleriyle Lp-PLA2 aktivitesi arasında zayıf güçte pozitif korelasyon saptanmıştır (r=0,311, p=0,000). Objective: The lack of validated, sensitive, and specific biomarkers for early diagnosis and follow-up of patients with malign melanoma (MM) is a major problem today. In this study, we aimed to investigate the correlations of two inflammatory biomarkers-serum amyloid A (SAA) and lipoprotein associated phospholipase A2 (Lp-PLA2)-in clinical follow-up and staging of MM. Methods: Lactate dehydrogenase (LDH) and C-reactive protein (CRP) (Routine), SAA and S100B (ELISA), and Lp-PLA2 (PLAC® Test) activity levels were examined in histologically and clinically confirmed MM patients (n=131) and in healthy controls (n=27). Results: Sedimentation rate and LDH, CRP, S100B, SAA, Lp-PLA2 activities were found to be significantly higher in MM patients compared to control group (p<0.05). SAA showed the strongest correlation with disease stage (Spearman’s correlation coefficient=0.622, p=0.000). Receiver operating characteristic analysis revealed that SAA exhibited the largest area under the curve=0.984, p=0.000, highest sensitivity (95%) and specificity (93%). Pearson’s test indicated a weak positive correlation between SAA levels and LpPLA2 activity (r=0.311, p=0.000). Conclusion: This is the first study to evaluate the activity of inflammatory biomarker Lp-PLA2 in melanoma patients. Both SAA and Lp-PLA2 were in highest levels in stage 4 patients, and they are thought to be candidate biomarkers to be used in detecting tumor progression. According to our results, SAA is the biomarker which correlates best with disease stage in MM.