Neurotoxic effects of low dose ranges of environmental metal mixture in a rat model: The benchmark approach.

Metals exert detrimental effects on various systems within the body, including the nervous system. Nevertheless, the dose-response relationship concerning the administration of low doses of metal mixtures remains inadequately explored. The assessment of neurotoxic effects of lead, cadmium, mercury, and arsenic mixture (MIX) administered at low dose ranges, was conducted using an in vivo approach. A subacute study was conducted on a rat model consisting of a control and five treatment groups subjected to oral exposure with gradually increasing doses (from MIX 1 to MIX 5). The results indicated that behavioural patterns in an already developed nervous system displayed a reduced susceptibility to the metal mixture exposure with tendency of higher doses to alter short term memory. However, the vulnerability of the mature brain to even minimal amounts of the investigated metal mixture was evident, particularly in the context of oxidative stress. Moreover, the study highlights superoxide dismutase's sensitivity as an early-stage neurotoxicity marker, as indicated by dose-dependent induction of oxidative stress in the brain revealed through Benchmark analysis. The narrowest Benchmark Dose Interval (BMDI) for superoxide dismutase (SOD) activity (1e-06 - 3.18e-05 mg As/kg b.w./day) indicates that arsenic may dictate the alterations in SOD activity when co-exposed with the other examined metals. The predicted Benchmark doses for oxidative stress parameters were very low, supporting "no-threshold" concept. Histopathological alterations were most severe in the groups treated with higher doses of metal mixture. Similarly, the brain acetylcholinesterase (AChE) activity demonstrated a dose-dependent decrease significant in higher doses, while BMDI suggested Cd as the main contributor in the examined metal mixture. These findings imply varying susceptibility of neurotoxic endpoints to different doses of environmentally relevant metal mixtures, advocating for risk assessment and regulatory measures to address metal pollution and enhance remediation strategies.

The Effects of Pregestational Overweight and Obesity on Maternal Lipidome in Pregnancy: Implications for Newborns' Characteristics.

Obesity is an important risk factor for the development of pregnancy complications. We investigated the effects of pregestational overweight and obesity on maternal lipidome during pregnancy and on newborns' characteristics. The study encompassed 131 pregnant women, 99 with pre-pregnancy body mass index (BMI) < 25 kg/m2 and 32 with BMI ≥ 25 kg/m2. Maternal lipid status parameters, plasma markers of cholesterol synthesis and absorption and sphingolipids were determined in each trimester. Data on neonatal height, weight and APGAR scores were assessed. The results showed a higher prevalence (p < 0.05) of pregnancy and childbirth complications among the participants with elevated pregestational BMI. Levels of total cholesterol, HDL-cholesterol (p < 0.05) and LDL-cholesterol (p < 0.01) were significantly lower, and concentrations of triglycerides were higher (p < 0.05) in women with increased pre-gestational BMI. Lower concentrations of the cholesterol synthesis marker, desmosterol, in the 2nd trimester (p < 0.01) and the cholesterol absorption marker, campesterol, in each trimester (p < 0.01, p < 0.05, p < 0.01, respectively) were also found in this group. Markers of maternal cholesterol synthesis were in positive correlation with neonatal APGAR scores in the group of mothers with healthy pre-pregnancy weight but in negative correlation in the overweight/obese group. Our results indicate that gestational adaptations of maternal lipidome depend on her pregestational nutritional status and that such changes may affect neonatal outcomes.

Cholesterol Metabolic Profiling of HDL in Women with Late-Onset Preeclampsia.

A specific feature of dyslipidemia in pregnancy is increased high-density lipoprotein (HDL) cholesterol concentration, which is probably associated with maternal endothelium protection. However, preeclampsia is most often associated with low HDL cholesterol, and the mechanisms behind this change are scarcely explored. We aimed to investigate changes in HDL metabolism in risky pregnancies and those complicated by late-onset preeclampsia. We analyze cholesterol synthesis (cholesterol precursors: desmosterol, 7-dehydrocholesterol, and lathosterol) and absorption markers (phytosterols: campesterol and ß-sitosterol) within HDL particles (NCSHDL), the activities of principal modulators of HDL cholesterol's content, and major HDL functional proteins levels in mid and late pregnancy. On the basis of the pregnancy outcome, participants were classified into the risk group (RG) (70 women) and the preeclampsia group (PG) (20 women). HDL cholesterol was lower in PG in the second trimester compared to RG (p < 0.05) and followed by lower levels of cholesterol absorption markers (p < 0.001 for campesterolHDL and p < 0.05 for ß-sitosterolHDL). Lowering of HDL cholesterol between trimesters in RG (p < 0.05) was accompanied by a decrease in HDL phytosterol content (p < 0.001), apolipoprotein A-I (apoA-I) concentration (p < 0.05), and paraoxonase 1 (PON1) (p < 0.001), lecithin-cholesterol acyltransferase (LCAT) (p < 0.05), and cholesterol ester transfer protein (CETP) activities (p < 0.05). These longitudinal changes were absent in PG. Development of late-onset preeclampsia is preceded by the appearance of lower HDL cholesterol and NCSHDL in the second trimester. We propose that reduced capacity for intestinal HDL synthesis, decreased LCAT activity, and impaired capacity for HDL-mediated cholesterol efflux could be the contributing mechanisms resulting in lower HDL cholesterol.

Effects of Apnea, Obesity, and Statin Therapy on Proprotein Convertase Subtilisin/Kexin 9 Levels in Patients with Obstructive Sleep Apnea.

OBJECTIVES: Obstructive sleep apnea (OSA) is a common condition closely related to obesity, insulin resistance, dyslipidemia, and cardiovascular disease. The aim of this study was to explore the possible relationship between OSA and proprotein convertase subtilisin/kexin type 9 (PCSK9). METHODS: Full-night polysomnography was performed on 150 participants who were divided into three groups: controls, OSA patients on statin therapy, and OSA patients not on statin therapy. Biochemical markers, plasma low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclasses, and PCSK9 were determined. RESULTS: PCSK9 was highest in OSA patients on statins compared to the control group and to OSA patients not on statins (p = 0.036 and p = 0.039, respectively), after adjustment for body mass index (BMI). LDL diameter was greater in OSA patients not on statins compared to OSA patients on statins (p = 0.032). PCSK9 was highest in the group of patients with all three risk factors (diagnosed OSA, statins, BMI ≥25 kg/m2) compared to groups with no, one, and two risk factors (p = 0.031, p = 0.001, and p = 0.029, respectively). Presence of OSA, statin therapy, and BMI ≥25 kg/m2 when combined were independently associated with higher levels of PCSK9 when adjusted for antihypertensive therapy, small dense LDL, and HDL 3c subclass (odds ratio = 2.849; interquartile range [1.026-7.912], p = 0.044). CONCLUSION: Statin therapy was closely related to PCSK9. OSA along with obesity and statin use induces elevation of PCSK9.

Prooxidant-antioxidant balance, hsTnI and hsCRP: mortality prediction in haemodialysis patients, two-year follow-up.

Oxidative stress and inflammation are highly intertwined pathophysiological processes. We analyzed the markers of these processes and high-sensitive troponin I (hsTnI) for mortality prediction in patients on haemodialysis. This study enrolled a total of 62 patients on regular haemodialysis. The patients were monitored for two years, and the observed outcomes were all-cause and cardiovascular mortality. Blood samples were taken before one dialysis session for analysis of the baseline concentrations of prooxidant-antioxidant balance (PAB), total antioxidant status (TAS), total oxidative status (TOS), hsTnI, hsCRP and resistin. The overall all-cause mortality was 37.1% and CVD mortality 16.1%. By univariate and multivariate logistic regression, our findings suggest that good predictors of all-cause mortality include hsCRP and PAB (p < .05) and of CVD mortality hsCRP (p < .05) and hsTnI (p < .001). To evaluate the relationship between the combined parameter measurements and all-cause/CVD mortality risk, patients were divided into three groups according to their PAB, hsCRP and hsTnI concentrations. The cutoffs for hsCRP and hsTnI and the median for PAB were used. Kaplan-Meier survival curves pointed out that the highest mortality risk of all-cause mortality was in the group with hsCRP levels above the cutoff and PAB levels above the median (p < .001). The highest risk of CVD mortality was found in the group with hsCRP and hsTnI levels above the cutoff levels (p = .001). Our data suggest that hsCRP and PAB are very good predictors of all-cause mortality. For CVD complications and mortality prediction in HD patients, the most sensitive parameters appear to be hsTnI and hsCRP.

Association of serum amyloid A and oxidative stress with paraoxonase 1 in sarcoidosis patients.

BACKGROUND: It has been reported that high-density lipoprotein (HDL) particles have anti-inflammatory and antioxidant roles thanks to different enzymes such as paraoxonase 1 (PON1). Under inflammatory and oxidative stress conditions, HDL particles may lose their protective properties. Sarcoidosis is an inflammatory disease characterized by excessive oxidative stress. Serum amyloid A (SAA) is produced in liver and in granulomas, and its concentration increases in inflammatory conditions contributing to increased catabolism of HDL particles. The aim of our study was to determine PON1 activity, SAA concentration and their associations in patients with sarcoidosis. MATERIALS AND METHODS: Inflammatory [high-sensitive C-reactive protein (hsCRP), angiotensin-converting enzyme (ACE), SAA], lipid [total cholesterol (TC), HDL-cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides (TG)] oxidative stress status parameters [total oxidant status (TOS), malondialdehyde (MDA), pro-oxidant-antioxidant balance (PAB), sulfhydryl (SH) groups] and PON1 activities were determined in serum of 72 patients with sarcoidosis and 62 healthy subjects. RESULTS: HsCRP (P < 0·05), TC, LDL-c, TG, SAA, TOS, MDA and PAB (P < 0·001) were significantly higher, whereas HDL-c, SH groups and PON1 activity (P < 0·001) were significantly lower in patients with sarcoidosis when compared with controls. PON1 showed significant association with SAA, MDA and PAB. It was shown that 71% of decrease in PON1 activity may be explained by increase in TOS, PAB and SAA concentration. CONCLUSIONS: We found decreased PON1 activity and increased SAA concentration in patients with sarcoidosis. Inflammatory condition presented by high SAA was implicated in impaired HDL functionality evident through dysregulated PON1 activity. Excessive oxidative stress was also involved in dysregulation of PON1 activity.

Associations of oxidative stress status parameters with traditional cardiovascular disease risk factors in patients with schizophrenia.

BACKGROUND: The purpose of this study was to assess oxidative stress status parameters and their possible associations with traditional cardiovascular risk factors in patients with schizophrenia, as well as their potential for patient-control discrimination. METHODS: Fasting glucose, lipid profile and oxidative stress status parameters were assessed in 30 schizophrenic patients with atypical antipsychotic therapy and 60 control subjects. RESULTS: Malondialdehyde (MDA), pro-oxidant/antioxidant balance (PAB) and total anti-oxidant status (TAS) were significantly higher whereas total sulfhydryl (SH) groups were significantly lower in schizophrenic patients vs. control group. Higher serum PAB values showed an independent association with schizophrenia. The addition of PAB to conventional risk factors improved discrimination between healthy control subjects and patients. CONCLUSION: Increased oxidative stress and changed lipid profile parameters are associated in schizophrenic patients and may indicate risk for atherosclerosis. The serum PAB level may reflect the levels of oxidative stress in schizophrenia and improve discrimination of patients from controls.

Effect of alpha-lipoic acid supplementation on oxidative stress markers and antioxidative defense in patients with schizophrenia.

BACKGROUND: The purpose of this study was to examine the effects of alpha-lipoic acid (LA) supplementation on oxidative stress markers in patients with schizophrenia. SUBJECTS AND METHODS: Eighteen (18) medicated patients with schizophrenia and 38 healthy controls received daily supplements of LA (500 mg/day) for three months. At baseline, 45th and 90th days of supplementation, venous blood collected for analysis of oxidative stress markers [superoxide anion (O2(•-)), thiobarbituric acid-reactive substances (TBARS) and advanced oxidation protein products (AOPP)] and antioxidative defense markers [superoxide dismutase (SOD), total sulfhydryl groups (-SH) and total antioxidant status (TAS)]. RESULTS: Increased plasma TBARS, TAS, SH groups levels and SOD activity were found in schizophrenic patients compared to control group. LA supplementation significantly reduced TBARS, AOPP and improved TAS levels in healthy subjects, while there were no significant differences in patients group. SH groups increased after 45 days and decreased to baseline levels after 90 days of supplementation in the control group. SOD activity decreased significantly in patients group after 45 days and 90 days of supplementation. After initial rose SOD activity in control group, decreased to baseline levels found after 90 days. CONCLUSION: LA supplementation decreased lipid peroxidation and oxidative damage of proteins and improved non-enzymatic antioxidant capacity in healthy controls. No significant changes were observed on oxidative damage in patients with schizophrenia.

Glutathione S-transferase A1, M1, P1 and T1 null or low-activity genotypes are associated with enhanced oxidative damage among haemodialysis patients.

BACKGROUND: Increased oxidative stress is a hallmark of end-stage renal disease (ESRD). Glutathione S-transferases (GST) are involved in the detoxification of xenobiotics and protection of oxidative damage. We hypothesized that genetic polymorphism in antioxidant enzymes GSTA1, GSTM1, GSTP1 and GSTT1 is more frequent in ESRD and modulates the degree of oxidative stress in these patients. METHODS: GSTA1, GSTM1, GSTP1 and GSTT1 genotypes were determined in 199 ESRD patients and 199 age- and gender-matched controls. Markers of protein and lipid oxidative damage [thiol groups, carbonyl groups, advanced oxidative protein products, nitrotyrosine, malondialdehyde (MDA) and MDA adducts], together with total oxidant status and pro-oxidant-antioxidant balance were determined. RESULTS: Individual GST polymorphisms influence vulnerability to both protein and lipid oxidation, with GSTM1-null gene variant having the most pronounced effect. Furthermore, a strong combined effect of null/low-activity GSTM1, GSTT1, GSTA1 and GSTP1 genotypes in terms of susceptibility towards oxidative and carbonyl stress was found in ESRD patients. When patients were stratified according to GSTM1 and GSTT1, the highest oxidant damage was noted in those with the GSTM1-null/GSTT1-null genotype. The observed effect was even stronger in patients with the third low-activity GSTP1 or GSTA1 genotype. Finally, the level of oxidative and carbonyl stress was most pronounced in the subgroup of patients with all four null or low-activity GSTM1, GSTT1, GSTP1 and GSTA1 genotypes. CONCLUSIONS: According to the GST genotype, ESRD patients may be stratified in terms of the level of oxidative and carbonyl stress that might influence cardiovascular prognosis, but could also improve efforts towards individualization of antioxidant treatment.

Effects of Gestational Diabetes Mellitus on Cholesterol Metabolism in Women with High-Risk Pregnancies: Possible Implications for Neonatal Outcome.

Metabolic disorders in pregnancy, particularly gestational diabetes mellitus (GDM), are associated with an increased risk for adverse pregnancy outcome and long-term cardiometabolic health of mother and child. This study analyzed changes of serum cholesterol synthesis and absorption markers during the course of high-risk pregnancies, with respect to the development of GDM. Possible associations of maternal lipid biomarkers with neonatal characteristics were also investigated. The study included 63 women with high risk for development of pregnancy complications. Size and proportions of small low-density (LDL) and high-density lipoprotein (HDL) particles were assessed across trimesters (T1−T3), as well as concentrations of cholesterol synthesis (lathosterol, desmosterol) and absorption markers (campesterol, ß-sitosterol). During the study, 15 women developed GDM, while 48 had no complications (non-GDM). As compared to the non-GDM group, women with GDM had significantly higher triglycerides in each trimester, while having a lower HDL-C level in T3. In addition, they had significantly lower levels of ß-sitosterol in T3 (p < 0.05). Cholesterol synthesis markers increased across trimesters in both groups. A decrease in serum ß-sitosterol levels during the course of pregnancies affected by GDM was observed. The prevalence of small-sized HDL decreased in non-GDM, while in the GDM group remained unchanged across trimesters. Newborn's size in the non-GDM group was significantly higher (p < 0.01) and inversely associated with proportions of both small, dense LDL and HDL particles (p < 0.05) in maternal plasma in T1. In conclusion, high-risk pregnancies affected by GDM are characterized by altered cholesterol absorption and HDL maturation. Advanced lipid testing may indicate disturbed lipid homeostasis in GDM.

Antioxidant status in hypertensive disorders of pregnancy.

OBJECTIVE: Pregnancy can be associated with maternal hypertension leading to possible complications in pregnancy outcome. Antioxidant status may be proned to changes during pregnancy with hypertension. The aim of our study was to estimate antioxidant status through high-risk pregnancies. METHODS: Seventy-nine pregnant women with high-risk for preeclampsia development were included and 46 of them developed some hypertensive disorder in pregnancy. Superoxide-dismutase (SOD) and paraoxonase 1 (PON1) activities and relative proportion of PON1 activiity on different HDL subclasses were determined in 1st, 2nd, and 3rd trimester and prior to delivery. RESULTS: SOD activity was significantly lower in 2nd and 3rd trimesters when compared to 1st trimester (P˂0.001) whereas PON1 activity was significantly higher in 3rd than in 1st trimester (P˂0.05) in group of hypertensive women. This group had significantly higher SOD and PON1 activities and relative proportion of PON1 on HDL3c subclasses in the 1st trimester, significantly increased PON1 in the 3rd trimester and prior to delivery and significantly higher PON1 activity on HDL3c subclasses (P˂0.05) than nonhypertensive group. In 1st trimester and prior to delivery, total PON1 activity and relative proportion of PON1 on HDL3c subclasses exhibited significant ability to mark out hypertension in pregnancy (P˂0.05). CONCLUSIONS: SOD activity decreased whereas total PON1 activity increased during pregnancy with hypertension. Pregnant women with hypertension had higher activities of PON1 and SOD and relative proportion of PON1 on HDL3c subclasses than nonhypertensive ones. PON1 activity and relative proportion of PON1 on HDL3c subclasses exhibited significant association with hypertension in pregnancy.

Unraveling the role of oxidative stress and lipid status parameters in the onset of preeclampsia.

OBJECTIVE: The aim of the study was to assess the potential role of oxidative stress and lipid status in the onset of preeclampsia.METHODS: 138 high-risk pregnant women were prospectively followed. Assessment of oxidative stress (TAS, TOS, AOPP and SH groups) and lipid status (t-C, LDL-C, HDL-C, TGC, APO-A1, APO-B) was carried out during the pregnancy.RESULTS: 30 women developed preeclampsia. TGC, atherogenic index of plasma, TAS and SH levels were higher in women who subsequently developed preeclampsia (p<0.05).CONCLUSION: Oxidative stress and lipid status disturbance have a potential role in the onset of preeclampsia in high risk pregnancies.

Effect of propolis and N-acetylcysteine supplementation on lipoprotein subclasses distribution and paraoxonase 1 activity in subjects with acute respiratory infection.

BACKGROUND: Propolis and N-acetylcysteine have positive impact on respiratory tract health. Also, it has been suggested that they have beneficial effects on serum lipid and oxidative stress status, but the available data are limited and mostly gained from animal models. In this study we evaluated the effects of propolis and N-acetylcysteine supplementation (PropoMucil®) on lipid status, lipoprotein subclasses distribution and paraoxonase 1 activity in subjects with acute respiratory infection. METHODS: Twenty subjects with acute respiratory infection were included. PropoMucil® granules for oral solution (80 mg of dry propolis extract and 200 mg of N-acetylcysteine) were administered tree times per day for ten days. Serum lipid profile, paraoxonase 1 activity and low-density and high-density lipoprotein size and subclasses distribution were assessed at baseline and after supplementation. RESULTS: Following ten days of supplementation lipid status remained unchanged, but a significant increase of low-density lipoprotein particle size and proportion of high-density lipoprotein 3a particles were found (P<0.05). Moreover, supplementation with PropoMucil® significantly improved high-density lipoprotein particles distribution, particularly in those who smoke. There was a moderate increase of paraoxonase 1 activity, but without statistical significance. CONCLUSIONS: The presented study demonstrated that short-term supplementation with PropoMucil® has beneficial effects on low-density and high-density lipoprotein subclasses distribution and paraoxonase 1 activity in subjects with acute respiratory infection particularly in those who smoke.

Increased Oxidized High-Density Lipoprotein/High-Density Lipoprotein-Cholesterol Ratio as a Potential Indicator of Disturbed Metabolic Health in Overweight and Obese Individuals.

BACKGROUND: We evaluated the qualitative characteristics of high-density lipoprotein (HDL) particles in metabolically healthy and unhealthy overweight and obese subjects. METHODS: The study involved 115 subject individuals classified as metabolically healthy and unhealthy, as in overweight and obese groups. Commercial enzyme-linked immunosorbent assay (ELISA) kits were used to measure oxidized HDL (OxHDL) and serum amyloid A (SAA) concentrations. Lipoprotein subfractions were separated using nondenaturing gradient gel electrophoresis. RESULTS: An independent association was shown between increased OxHDL/HDL-cholesterol ratio and the occurrence of metabolically unhealthy phenotype in the overweight and obese groups. The OxHDL/HDL-cholesterol ratio showed excellent and acceptable diagnostic accuracy in determination of metabolic health phenotypes (overweight group, AUC = 0.881; obese group, AUC = 0.765). Accumulation of smaller HDL particles in metabolically unhealthy subjects was verified by lipoprotein subfraction analysis. SAA concentrations did not differ significantly between phenotypes. CONCLUSIONS: Increased OxHDL/HDL-cholesterol ratio may be a potential indicator of disturbed metabolic health in overweight and obese individuals.

Paraoxonase 1 and atherosclerosis-related diseases.

A direct and an indirect relationship between paraoxonase 1 (PON1) and atherosclerosis exists. Given PON1's physical location within high-density lipoprotein (HDL) particles and its recognized enzyme activity, it is certainly reasonable to suggest that PON1 facilitates the antiatherogenic nature of HDL particles. PON1 also plays a role in regulating reverse cholesterol transport, antioxidative, anti-inflammatory, antiapoptotic, vasodilative, and antithrombotic activities and several endothelial cell functions. HDL dysfunctionality is a more recent issue and seems to be centered on pathological conditions affecting HDL structure and size profiles. This review is focused on the role of PON1 status in different atherosclerosis-related diseases that we have studied over the last twenty years (coronary heart disease, acute ischemic stroke, diabetes mellitus type 2, end-stage renal disease, chronic obstructive pulmonary disease, and sarcoidosis) with the aim to determine the true value of PON1 as a biomarker. The role of PON1 in cancer is also covered, as risk factors and mechanisms underlying both atherosclerosis and cancer share common features.

Association of Nrf2, SOD2 and GPX1 Polymorphisms with Biomarkers of Oxidative Distress and Survival in End-Stage Renal Disease Patients.

The oxidative stress response via Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) interlinks inflammation- and metabolism-related pathways in chronic kidney disease. We assessed the association between polymorphisms in Nrf2, superoxide dismutase (SOD2), glutathione peroxidase (GPX1), and the risk of end-stage renal disease (ESRD). The modifying effect of these polymorphisms on both oxidative phenotype and ESRD prognosis, both independently and/or in combination with the glutathione S-transferase M1 (GSTM1) deletion polymorphism, was further analyzed. Polymorphisms in Nrf2 (rs6721961), SOD2 (rs4880), GPX1 (rs1050450), and GSTM1 were determined by PCR in 256 ESRD patients undergoing hemodialysis and 374 controls. Byproducts of oxidative stress were analyzed spectrophotometically or by ELISA. Time-to-event modeling was performed to evaluate overall survival and cardiovascular survival. The SOD2 Val/Val genotype increased ESRD risk (OR = 2.01, p = 0.002), which was even higher in combination with the GPX1 Leu/Leu genotype (OR = 3.27, p = 0.019). Polymorphism in SOD2 also showed an effect on oxidative phenotypes. Overall survival in ESRD patients was dependent on a combination of the Nrf2 (C/C) and GPX1 (Leu/Leu) genotypes in addition to a patients' age and GSTM1 polymorphism. Similarly, the GPX1 (Leu/Leu) genotype contributed to longer cardiovascular survival. Conclusions: Our results show that SOD2, GPX1, and Nrf2 polymorphisms are associated with ESRD development and can predict survival.

Association between proprotein convertase subtilisin/kexin 9 (PCSK9) and lipoprotein subclasses in children with type 1 diabetes mellitus: Effects of glycemic control.

BACKGROUND AND AIMS: Dyslipidemia in type 1 diabetes mellitus (T1DM) is characterised by altered distributions of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclasses. Recent studies suggested that proprotein convertase subtilisin/kexin 9 (PCSK9) may contribute to the development of dyslipidemia in T1DM. In this cross-sectional study, we investigated the association between PCSK9 and lipoprotein subclasses in young T1DM patients, with respect to glycemic control. METHODS: Plasma PCSK9 and lipoprotein subclasses were determined in 207 patients with T1DM (106 boys and 101 girls), aged 13.9 ±â€¯3.0 years and treated by intensive insulin therapy. RESULTS: Plasma PCSK9 levels significantly increased with worsening of glycemic control (p < 0.001). T1DM patients with poor glucoregulation had the highest proportion of small, dense LDL (sdLDL) and smaller HDL particles, as well. PCSK9 was positively associated with markers of glucose homeostasis and serum lipid parameters only in patients with suboptimal/poor glucoregulation. In well-controlled T1DM, plasma PCSK9 level was inversely associated with a relative proportion of sdLDL particles (p < 0.01) and this association remained significant in multivariate analysis. In T1DM patients with suboptimal/poor glycemic control, PCSK9 was positively associated with the proportion of the smallest HDL3c particles (p < 0.001), but negatively with HDL size (p < 0.05). CONCLUSIONS: The extent of achieved metabolic control modifies the association between PCSK9 and lipoprotein subclasses in T1DM. Further investigations are needed to reveal whether the observed effects of glycemic control on PCSK9 and sdLDL levels have causal consequences on CVD risk in young patients with T1DM.

Association Between Superoxide Dismutase Isoenzyme Gene Expression and Total Antioxidant Status in Patients with an End-Stage Renal Disease

Background: Chronic renal failure, particularly end-stage renal disease, is a serious health problem associated with a high mortality rate. Uremic syndrome leads to increased oxidative stress, inflammation, and dyslipidemia. Aims: To examine superoxide dismutase isoenzyme gene expression in peripheral blood mononuclear cells of patients on hemodialysis and to determine the associations between superoxide dismutase isoenzyme gene expression, oxidative stress, and non-enzymatic antioxidative protection. Study Design: Case control study. Methods: This study included 33 patients on hemodialysis (age, 55.33±15.31 years old) and 33 apparently healthy controls (age, 45.37±8.92 years old). Superoxide dismutase isoenzyme messenger ribonucleic acid levels were determined by real-time polymerase chain reaction. General biochemical parameters, high sensitivity C-reactive protein, total antioxidant status, thiobarbituric acid-reactive substances, and the superoxide anion radical were also determined. Results: Normalized Cu/Zn superoxide dismutase and Mn superoxide dismutase messenger ribonucleic acid levels were significantly higher in patients than controls (p<0.001 and p=0.011). A significant negative correlation was detected between normalized Cu/Zn superoxide dismutase messenger ribonucleic acid levels and total protein, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total antioxidant status. Normalized Mn superoxide dismutase messenger ribonucleic acid levels were negatively correlated with total protein and total antioxidant status. A multiple regression analysis revealed independent associations between total antioxidant status and normalized Cu/Zn superoxide dismutase (p=0.038) and between total antioxidant status and normalized Mn superoxide dismutase messenger ribonucleic acid levels (p=0.038 and p=0.018, respectively). Conclusion: The superoxide dismutase isoenzyme gene is expressed at a higher rate in patients with end-stage renal failure, probably due to increased oxidative stress and attenuated antioxidative defense. The plasma total antioxidant status is an independent predictor of normalized superoxide dismutase isoenzyme messenger ribonucleic acid levels.

Associations of lipoprotein subclasses and oxidative stress status in pulmonary and pulmonary plus extrapulmonary sarcoidosis.

Background: Sarcoidosis is an inflammatory disease with pulmonary and extrapulmonary manifestations. In such pathologic conditions, increased oxidative stress and rearrangement of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) may occur. Objective: This study evaluated association of oxidative stress and lipoprotein subclasses in severe forms of pulmonary and pulmonary plus extrapulmonary sarcoidosis. Methods: Lipid parameters, LDL and HDL subclass distributions, high-sensitivity C-reactive protein (hsCRP), serum amyloid A (SAA), paraoxonase 1 (PON1), malondialdehyde (MDA), total-oxidant status (TOS), sulfhydryl (SH) groups, pro-oxidant anti-oxidant balance (PAB) were determined in 77 patients (53 isolated pulmonary and 24 pulmonary plus extrapulmonary) and 139 controls. Results: Both pulmonary and extrapulmonary sarcoidosis patients had significantly higher levels of triglycerides and TOS (P<0.05) and more LDL II, LDL III, LDL IVA particles (P<0.01), but lower HDL size, SH groups (P<0.001), PON1 activity and less LDL I subclasses (P<0.05) than controls. In isolated pulmonary disease, HDL-cholesterol (P<0.01) was significantly lower whereas proportions of HDL 3a and PAB were significantly higher (P<0.05) when compared with the control group. PON1 was significantly higher in pulmonary than in combined pulmonary-extrapulmonary disease (P<0.05). In pulmonary sarcoidosis, TOS and PON1 correlated significantly with small-sized HDL particles (P<0.05). Conclusions: Both patient groups were characterized by adverse lipoprotein profile and elevated oxidative stress. In isolated pulmonary group significant associations of oxidative stress and HDL particles distribution was demonstrated. Pulmonary sarcoidosis was associated with higher PON1 activity and rearrangement of LDL particles did not depend on disease localization. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 198-205).

Effects of co-existing autoimmune diseases on serum lipids and lipoprotein subclasses profile in paediatric patients with type 1 diabetes mellitus.

OBJECTIVE: Paediatric patients with type 1 diabetes mellitus (T1DM) frequently develop other autoimmune disorders; most commonly autoimmune thyroiditis (ATD) and celiac disease (CD). In this study we evaluated whether co-existing autoimmune diseases had significant impact on lipid and lipoprotein subclasses, as known cardiovascular risk factors in T1DM. DESIGN AND METHODS: Study included 201 subjects with T1DM (14.1 ±â€¯2.9 years) and 141 age- and gender-matched controls. ATD was presented in 30 and CD in 15 T1DM patients. Serum lipid parameters were determined by routine laboratory methods and plasma low-density (LDL) and high-density lipoprotein (HDL) subclasses by gradient-gel electrophoresis method. RESULTS: Both groups of T1DM patients with concomitant autoimmune disease had significantly lower HDL-C levels (P < 0.05) than the patients with T1DM only, but comparable to control group (P = 0.436). T1DM patients had significantly higher (P < 0.001) proportion of small HDL subclasses than controls. Mean value of atherosclerosis index in patients with T1DM + CD was the highest (1.75 ±â€¯0.86) and it was significantly higher than the index in patients with T1DM only (1.33 ±â€¯0.51; P < 0.05). LDL size did not differ between the groups of T1DM patients and control group (P = 0.619). The size of HDL particles was significantly reduced (P < 0.05) in the groups with associated autoimmune diseases. The patients with co-existing autoimmune diseases had higher risk of low HDL-C level (OR: 2.96; P < 0.05). CONCLUSIONS: The results have shown significant impact of co-existing autoimmune diseases on lipid profile in patients with T1DM. The most prominent changes were found in HDL lipoprotein characteristics in T1DM + CD group.