Nahla N Younis

Variation in paraoxonase-1 activity and atherosclerosis.

Purpose of review Paraoxonase-1 (PON1) is an HDL-associated protein of 354 amino acids with a molecular mass of 43 000 Da. It is synthesized in the liver, and in serum it is almost exclusively associated with HDL. PON1 has been reported to be an important contributor to the antioxidant and anti-inflammatory activities of HDL. PON1 impedes oxidative modification of LDL. PON1 serum activity is related to systemic lipid peroxidation stress and prospective cardiovascular risk. In this review, we discuss the relationship between PON1 activity and atherosclerotic diseases and various factors modulating PON1 activity including genes, age, lifestyle factors and medical conditions. Finally, evidence that pharmacological agents may affect PON1 activity is summarized. Recent findings There is increasing evidence from both animal and human studies linking low PON1 activity to an increased likelihood of cardiovascular diseases. Two prospective studies reported a significantly lower incidence of major cardiovascular events in participants with the highest systemic PON1 activity, compared with those with the lowest activity. Summary PON1 is a potentially antiatherogenic HDL-associated enzyme that protects LDL from oxidative modification. Enhancing PON1 activity could be an important target for future pharmacological agents aimed at decreasing cardiovascular risk.

Glycation of LDL in non-diabetic people: Small dense LDL is preferentially glycated both in vivo and in vitro

OBJECTIVE LDL atherogenicity is frequently attributed to oxidative modification, but glycated LDL, which can participate in many of the cellular processes leading to atherosclerosis, generally circulates at higher concentration even in non-diabetic people. We tested the hypothesis that small-dense LDL, known to be most closely associated with coronary heart disease, undergoes more glycation than other LDL sub-fractions. METHODS AND RESULTS The concentration of glycated apolipoprotein B (apo B) was measured in serum, LDL and its sub-fractions from 44 non-diabetic subjects. By ELISA serum glycated apoB concentration was 3.0+/-1.1mg/dl (mean+/-S.D.) of which 84.6+/-13.6% was in LDL. Of the glycated apo B in LDL 67.8+/-21.9% was in small dense LDL (LDL3; D1.044-1.063g/ml) whereas only 32.2+/-21.9% was in more buoyant LDL subfractions (LDL1 and 2; D1.019-1.044g/ml). The percentage of apo B present in LDL1 and 2 which was glycated was 1.8+/-1.8% whereas in LDL3 it was 17.4+/-18.5% (P<0.001). Furthermore when LDL sub-fractions from non-diabetics (n=29) were incubated with glucose (30-80mmol/l) glycation of apo B in the denser LDL3 subfraction was significantly more pronounced than in less dense LDL subfractions. CONCLUSION Small-dense LDL is more susceptible to glycation and this may contribute to the atherogenicity of small-dense LDL, even in non-diabetic people.

Glycation as an atherogenic modification of LDL

Purpose of review To highlight the potential importance of glycation as an atherogenic modification of LDL in both diabetic and nondiabetic people. Recent findings Small dense LDL which is known to be most closely associated with atherogenesis is more susceptible to glycation than more buoyant LDL. Glycation and oxidation of LDL appear to be intimately associated. Summary Glycation of LDL occurs chiefly due to the nonenzymatic reaction of glucose and its metabolites with the free amino groups of lysine in which LDL is rich. Higher concentrations of glycated LDL are present in diabetic than in nondiabetic individuals, but even in the latter, there is generally more circulating glycated LDL than oxidatively modified LDL. Probably, oxidation and glycation of LDL are at least partially interdependent, but both prevent LDL receptor-mediated uptake and promote macrophage scavenger receptor uptake. The recognition that LDL glycation is at least as important as oxidation in atherogenesis may lead to improvements in our understanding of its mechanism and how to prevent it.

Small-dense LDL and LDL glycation in metabolic syndrome and in statin-treated and non-statin-treated type 2 diabetes:

Small-dense LDL (SD-LDL) has been particularly implicated in atherosclerosis. It has previously been reported that in non-diabetic people SD-LDL is preferentially glycated. The distribution of glycated apolipoprotein B (glyc-apoB) in lipoproteins in metabolic syndrome (MS) and in type 2 diabetes has not previously been studied. Plasma apoB and glyc-apoB were determined in different apoB-containing lipoproteins including buoyant and SD-LDL in MS (n=18) and type 2 diabetes (DM) [n=48; 12 statin-untreated (DM−S) and 36 statin-treated (DM+S)]. Plasma glyc-apoB was 5.6 ± 0.9, 3.5 ± 0.5 and 4.0 ± 0.2 mg/dl in DM−S, DM+S and MS, respectively. The glycated proportion of SD-LDL-apoB was greater than buoyant LDL in all groups. SD-LDL contributed most to plasma glyc-apoB in DM−S, because SD-LDL-apoB was higher in DM−S than in MS and DM+S (p < 0.001). Plasma glyc-apoB correlated with SD-LDL-apoB (r=0.74, p < 0.0001 in diabetes and r=0.53, p < 0.001 in MS), but not with HbA1c. SD-LDL is preferentially glycated in type 2 diabetes and MS. Its concentration is a stronger determinant of plasma glycapoB than glycaemia. Statin-induced changes in its level may be important in decreasing apoB glycation in diabetes. These findings may explain the small effect of improving glycaemia relative to statin treatment in reducing atherosclerosis risk in type 2 diabetes and the increased risk in MS even before the onset of type 2 diabetes.

Small dense LDL is more susceptible to glycation than more buoyant LDL in Type 2 diabetes

Glycation of apoB (apolipoprotein B) of LDL (low-density lipoprotein) increases its atherogenicity. Concentrations of both serum glyc-apoB (glycated apoB) and SD-LDL (small dense LDL) (syn LDL3; D=1.044-1.063 g/ml) are increased in diabetes and are closely correlated. We studied whether SD-LDL is more susceptible to glycation in vitro than more buoyant LDL in statin- and non-statin-treated Type 2 diabetes mellitus. Serum SD-LDL apoB and glyc-apoB on statins was 20±2 (means±S.D.) and 3.6±0.41 compared with 47±3 and 5.89±0.68 mg/dl in those not receiving statins (P<0.001 and <0.01, respectively). There was a dose-dependent increase in glycation on incubation of LDL subfractions with glucose, which was accompanied by an increase in LPO (lipid peroxide) and electrophoretic mobility and a decrease in free amino groups. SD-LDL was more susceptible to these changes than more buoyant LDL. Both SD-LDL and more buoyant LDL from statin-treated patients were less susceptible to glycation. There were fewer free amino groups on LDL subfractions from statin-treated patients, which may contribute to this resistance. In conclusion, greater susceptibility of SD-LDL to glycation is likely to contribute to the raised levels of circulating glyc-apoB in diabetes. Statins are associated with lower levels of both SD-LDL and glyc-apoB.

High-density lipoprotein impedes glycation of low-density lipoprotein

Glycation of low-density lipoprotein (LDL) increases its atherogenicity, but whether high-density lipoprotein (HDL) can protect LDL against glycation is not known. LDL and HDL were isolated from 32 volunteers with serum HDL cholesterol concentrations ranging from 0.76 to 2.01 (mean = 1.36) mmol/L. Glycation of LDL was induced by incubation with 0–80 mmol/L glucose for 7 days at 37°C under nitrogen in the presence of and absence of human HDL. Glycation of LDL apolipoprotein B (apoB) doubled at glucose 50 and 80 mmol/L (both p < 0.001), and this increase was ameliorated by HDL. In the absence of glucose, 0.11 (0.01) [mean (standard error, SE)] mg apoB/mg LDL protein was glycated increasing to 0.22 (0.02) mg/mg at glucose 80 mmol/L in the absence of HDL, but remaining at 0.13 (0.01) mg/mg when autologous HDL was present. Heterologous HDL from a further study of 12 healthy participants was similarly effective in impeding LDL apoB glycation. HDL impeded not only glycation but also the lipid peroxidation, free amino group consumption and increased electrophoretic mobility of LDL which accompanied glycation. HDL from participants with higher serum paraoxonase1 (PON1) was more effective in impeding glycation and the related processes. In conclusion, HDL can impede the glucose-induced glycoxidation of LDL. PON1 may be important for this function of HDL.

Apolipoprotein B100 is a better treatment target than calculated LDL and non-HDL cholesterol in statin-treated patients.

Introduction Clinical trials have shown that apolipoprotein B100 (apoB) is better than calculated low-density lipoprotein cholesterol (c-LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) as a target for statin treatment. However, there are no published reports of how well these targets are reached in patients with more severe hyperlipidaemias than represented in trials, as seen in lipid clinics. Methods We audited 195 patients attending a tertiary centre lipid clinic, who had been treated with a statin for more than one year. We measured total cholesterol, HDL-cholesterol (HDL-C) and triglyceride and from these calculated LDL-cholesterol (LDL-C) and non-HDL-C. We determined the average measured apoB values, at critical target values of LDL-C and non-HDL-C, by linear regression and compared them with values of apoB considered equivalent to these cholesterol indexes by expert groups. We also assessed the number of patients, both before and after treatment, in whom c-LDL-C and non-HDL-C could not be calculated due to hypertriglyceridaemia. Results At the LDL-C target of 2.6 mmol L−1 and the non-HDL-C target of 3.4 mmol L−1, the measured apoB values were significantly higher than consensus apoB target values. The difference was most marked for c-LDL-C in hypertriglyceridaemic subjects and for non-HDL-C in patients without hypertriglyceridaemia. A similar pattern was seen using centile-derived consensus values but the differences were accentuated because this approach generates lower equivalent consensus apoB values. Conclusion ApoB offers a more consistent treatment target independent of hypertriglyceridaemia and would obviate technical problems related to high triglycerides.

Lipoprotein glycation in atherogenesis

Abstract There has been increasing interest in investigating the role of glycation as an atherogenic modification of lipoproteins; especially after the failure of antioxidant therapy to suppress the incidence of atherogenic cardiovascular diseases in high-risk individuals. Glycation of lipoproteins impairs their function. In the case of LDL, it also leads to rapid scavenger-receptor uptake by monocyte/macrophages. Glycation also diminishes the antiatherogenic properties of HDL. The concentration of circulating glycated LDL, even in nondiabetics, is higher than that of oxidatively modified LDL. Glycated small dense LDL is significantly higher in nondiabetic individuals as well as in Type 2 diabetic patients. Lowering the level of small dense LDL by using statins lowers glycated LDL in Type 2 diabetic patients. This may be one of the reasons for their effect in decreasing cardiovascular risk in these patients. Treatments that prevent glycation of lipoproteins may prevent atherosclerosis and other diabetic complications.

HDL functionality in diabetes mellitus: potential importance of glycation

The incidence of atherosclerotic cardiovascular diseases correlates negatively with HDL. HDL has multiple potentially antiatherogenic properties that may be impaired in diabetes mellitus; in partciular, glycation of HDL could render it functionally deficient. This review explores the possible atheroprotective properties of HDL, the effect of diabetes mellitus and glycation on these properties and therapeutic interventions which could potentially reverse unfavorable deficiencies in HDL functionality.

Mesenchymal stem cells and 10-dehydrogingerdione in cisplatin induced renal fibrosis: A potential therapeutic target

Background: Sickle cell disease is associated with several systemic complications and life-threatening crises. The use of drugs that increase hemoglobin F level, such as hydroxyurea, in patients with sickle cell disease is associated with a reduction in the severity of the disease. Aim: To compare the outcome of patients adherent to hydroxyurea with those who are poorly adherent and to determine which age group is more likely to be poorly adherent and hence suffer more complications. Subjects and Methods: A cross-sectional study was performed at King Khalid University Hospital in Riyadh between January 01 and March 31, 2014. The study included 140 patients, 60 of them were receiving hydroxyurea therapy. Results: Patients who were adherent to hydroxyurea treatment suffered less complications and had less frequent sickling crises than patients who were poorly adherent to therapy. Patients belonging to the age group 15 to 30 years were found to be less adherent to treatment than other age groups and consequently they suffered more complications. Conclusion: More attention and health education should be offered to adolescents and young adults having sickle cell anemia in order for these patients to benefit from the positive impact of hydroxyurea on the disease outcome.Forty five rats were divided into the following groups (15 each): Group I was served as a control group, Group II was subgrouped to IIa, b and c, that were administered oral 50, 100 and 150 mg/kg of Diclofenac Sodium (DS) respectively for 2 days after fasting for 20 hours. Group III was subgrouped to IIIa, b and c. These rats were maintained on oral Moringa Oleifera (MO) (500mg/kg) daily for one week and then they were administered the same doses as in the previous group. Transmission electron microscopy (TEM) showed several alterations in the villous absorptive cell epithelial cells. These changes were mainly separation between two adjacent cells, degeneration and mitochondrial damage. Moreover, plasma cells and eosinophils were observed in the lamina properia. Administration of MO resulted in organization of microvilli, increase in goblet cell numbers with extruding their content into the lumen, abundant mitochondria in the cytoplasm of absorptive cells. It is also noticed that the inflammatory cells appeared tightly contact with the lamina properia. Morphometric analysis showed significant increase in the numbers of goblet cells especially in the groups received voltaren and MO. In conclusion the current study showed that MO leaves might have a partial protective effect on the rat duodenal mucosal histological changes resulted from the administration of high doses of diclofenac sodium in rat.