Susceptibility Of Low-density Lipoprotein Research Articles

We Must Abandon the Myth: Oxidized Low-density Lipoprotein is not a Lipoprotein that Plays a Key Role in Atherogenesis.

The purpose of this review is to revisit in detail the arguments supporting or disproving the hypothesis that oxidized low-density lipoprotein (LDL) plays a key role in atherosclerotic lesion development. The detection of oxidized LDL in vivo was extremely important for confirming its key role in atherogenesis. Indirect evidence of its existence included the presence of autoantibodies against malondialdehyde-treated LDL in human blood; however, the affinity of circulating antibodies to another LDL modification, such as desialylated LDL, was an order of magnitude stronger. At least 3 forms of atherogenic modified lipoproteins were isolated from the blood of atherosclerotic patients using different methods, namely, small dense, electronegative and desialylated. Their properties were so similar that it was suggested that the three types could be classified as the same multiple-modified LDL particle. It has been shown that when native (unmodified) LDL is incubated with autologous serum from patients with atherosclerosis, multiple modifications occur, which include desialylation, a decrease in the content of phospholipids and neutral lipids, a decrease in particle size, an increase in negative charge and other physical and chemical changes. Longer incubation also increased the susceptibility of LDL to oxidation. Thus, LDL oxidation is not the only, much less the most important, form of atherogenic modification of LDL since it occurs at the last stages of multiple modifications cascade and does not significantly increase the atherogenic potential of multiple-modified LDL. Finally, clinical trials did not support the oxidative hypothesis; however, research on oxidized LDL continues, influencing the future research. It is time to abandon the myth!

Protective effects of paraoxonase-1, vitamin E and selenium, and oxidative stress index on the susceptibility of low density lipoprotein to oxidation in diabetic patients with/without coronary artery disease

BackgroundThe oxidative modification of low density lipoprotein (LDL) is closely associated with an increased risk for coronary artery disease (CAD) in diabetic patients. The purpose of this study is to investigate the relation between serum vitamin E and selenium, paraoxonase-1 (PON1) activity, total antioxidant capacity (TAC), total oxidant status (TOS), malondialdehyde (MDA), and oxidative stress index (OSI) values with the susceptibility of LDL to oxidative modification and the possibility of CAD in diabetic patients.MethodThis study was designed as a case control survey of 82 diabetes patients divided into two groups including T2DM alone (as group I) and both T2DM and CAD (as group II). Fasting blood samples were taken to the assay of fasting blood glucose (FBG), HbA1c, total cholesterol (TC), TAC, TOS, MDA, OSI, vitamin E, selenium, oxidized low density lipoprotein (Ox-LDL), and activity of PON1.ResultsOx-LDL, MDA, TOS, and OSI values in groups II were significantly higher compared with group I (all with P value = 0.000). TAC, vitamin E, selenium, and PON1 activity values were significantly lower in group II compared with groups I (P value = 0.000; P value = 0.000; P value = 0.007; P value = 0.003, respectively). There were significant relationships between the amounts of TAC, TOS, OSI, and vitamin E with the amounts of PON1 activity and Ox-LDL (p < 0.05). But Ox-LDL and PON1 activity correlated weakly with together (p = 0.094).ConclusionResults of this study support the belief that oxidative stress might be an important etiologic factor which makes some diabetics more susceptible to CAD. Increased oxidative stress may be a potential therapeutic target in the prevention and management of CAD in diabetic patients.

Dysfunctional antioxidant capacity of high-density lipoprotein in rheumatoid arthritis.

High-density lipoprotein (HDL) presents atheroprotective functions not readily reflected by plasma HDL-cholesterol levels. The aim of this study was to investigate HDL antioxidant function in patients with rheumatoid arthritis (RA). This pilot and cross-sectional study included 50 RA patients and 50 controls matched by age, gender, cardiovascular risk factors and drug therapy. The antioxidant capacity of HDL was assessed by the total radical-trapping antioxidative potential test (TRAP-assay) and the susceptibility of low-density lipoprotein (LDL) to oxidation by the Conjugated Dienes Assay (Dmax ). A carotid ultrasound was performed in all participants to detect subclinical atherosclerosis. High-density lipoprotein from RA patients showed lower antioxidant capacity than those from controls [oxidized-LDL%: 35.8 (27-42) vs. 24.4 (20-32), p < .001] when analysed with the TRAP-assay. In addition, the time to achieve 50% of maximal LDL oxidation (Lag-time) was shorter in RA-patients than in matched controls [57.2 (42-71) vs. 69.5 (55-75) minutes, (p = .003)]. RA patients showed a higher atherosclerotic burden than controls. The pro-oxidant pattern in RA was irrespective of the presence of carotid atherosclerosis. On the contrary, there was a positive correlation between inflammatory parameters (erythrocyte sedimentation rate, ultrasensitive C-reactive protein and fibrinogen) and the loss of HDL-anti-oxidant capacity measured by the TRAP-assay (rho = .211, p = .035; rho = .231, p = .021 and rho = .206, p = .041, respectively). Furthermore, the glucocorticoid dose at recruitment was negatively associated with the Lag-time in RA patients (rho = -.387, p = .026). Rheumatoid arthritis patients present reduced HDL antioxidant capacity and a lower resistance of LDL particles to oxidation, mainly related to the degree of inflammation.

The human liver lipidome is significantly related to the lipid composition and aggregation susceptibility of low-density lipoprotein (LDL) particles

Background and aimsThe susceptibility of low-density lipoprotein (LDL) to aggregation predicts atherosclerotic cardiovascular disease. However, causes of interindividual variation in LDL lipid composition and aggregation susceptibility remain unclear. We examined whether the lipid composition and aggregation susceptibility of LDL reflect the lipid composition of the human liver. MethodsLiver biopsies and blood samples for isolation of LDL particles were obtained from 40 obese subjects (BMI 45.9 ± 6.1 kg/m2, age 43 ± 8 years). LDL was isolated using sequential ultracentrifugation and lipidomic analyses of liver and LDL samples were determined using ultra-high performance liquid chromatography–mass spectrometry. LDL aggregation susceptibility ex vivo was analyzed by inducing aggregation by human recombinant secretory sphingomyelinase and following aggregate formation. ResultsThe composition (acyl carbon number and double bond count) of hepatic triglycerides, phosphatidylcholines, and sphingomyelins (SMs) was closely associated with that of LDL particles. Hepatic dihydroceramides and ceramides were positively correlated with concentrations of the corresponding SM species in LDL as well with LDL aggregation. These relationships remained statistically significant after adjustment for age, sex, and body mass index. ConclusionsLipid composition of LDL reflects that of the human liver in obese patients. Changes in hepatic sphingolipid metabolism may contribute to interindividual variation of LDL lipid composition and susceptibility to aggregation.

Electronic and Tobacco Cigarettes Alter Polyunsaturated Fatty Acids and Oxidative Biomarkers.

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Aggregation Susceptibility of Low-Density Lipoproteins-A Novel Modifiable Biomarker of Cardiovascular Risk.

Circulating low-density lipoprotein (LDL) particles enter the arterial intima where they bind to the extracellular matrix and become modified by lipases, proteases, and oxidizing enzymes and agents. The modified LDL particles aggregate and fuse into larger matrix-bound lipid droplets and, upon generation of unesterified cholesterol, cholesterol crystals are also formed. Uptake of the aggregated/fused particles and cholesterol crystals by macrophages and smooth muscle cells induces their inflammatory activation and conversion into foam cells. In this review, we summarize the causes and consequences of LDL aggregation and describe the development and applications of an assay capable of determining the susceptibility of isolated LDL particles to aggregate when exposed to human recombinant sphingomyelinase enzyme ex vivo. Significant person-to-person differences in the aggregation susceptibility of LDL particles were observed, and such individual differences largely depended on particle lipid composition. The presence of aggregation-prone LDL in the circulation predicted future cardiovascular events in patients with atherosclerotic cardiovascular disease. We also discuss means capable of reducing LDL particles’ aggregation susceptibility that could potentially inhibit LDL aggregation in the arterial wall. Whether reductions in LDL aggregation susceptibility are associated with attenuated atherogenesis and a reduced risk of atherosclerotic cardiovascular diseases remains to be studied.

Synergistic Efficacy of Aframomum Melegueta [Roscoe] K. Schum and Spondias mombin (Linn), a Predictive Treatment of SARS-CoV-2 (COVID-19) Infection

SARS-CoV-2 is closely related to the original SARS-CoV. It is thought to have animal based origin from Bats(Betacoronavirus) in subgenus (Sarbecoronavirus) together with two bat-derived strains The virus is mainly spread between people during physical contact, often through small droplets produced during coughing, sneezing, even talking to patient or infected people. It is primarily spread during close contact and via small droplets produced when infected people cough, sneeze or talk with close contact being within 1–3 m (3 ft 3 in–9 ft 10 in). Those infected with the virus may be asymptomatic (Appearance of No symptoms) or develop flu-like symptom which include fever, cough, fatigue, and shortness of breath. The exposure time to initial symptom is day five (5 days). Majority of cases result in mild symptoms, some progress to viral pneumonia and multiple organ failure. Two medicinal plants may be used for the treatment of SARS-CoV-2, the two medicinal plants are Aframomum melegueta and Spondis mombin (Linn). Both contains arrays of natural product that may be used for drug formulation to combat SARS-CoV-2, Aframomum melegueta medicinal plant belong to the family Zingiberaceae which can be used to detoxify liver and bronchitis during lungs infection. Aframomum melegueta contains 6-Gingerol, 8-Gingerol, Methyl-6-Gingerol, 6-Shogaol, 6-Rac-6-Dihydro paradol,6-Gingeredione, 2-(5 butylfuran-2-yl) ethyl}-2-methoxyphenol and 6-Paradol. Secondary metabolite(Phytochemical)investigations of Aframomum melegueta extracts revealed the presence of (-)-buplerol, (-)-arctigenin, (E)- 14-hydroxy-15-norlabda-8(17), 12-dien- 16-al, labda-8(17), 12-dien-15, 16- dial, 16-oxo-8(17), 12(E)-labdadien-15-oic acid, 5-hydroxy-7-methoxy flavone and apigenin, The combination of all this novel compound can be used for the treatment of SARS-CoV-2. Spondias mombin belongs to the family of Anacardiaceae medicinal plants and contains Catechin and Epigalocatechin, Epicatechin, Stigmasterol and Phytosterol, a very important flavonoid that can be used in drug formulation because of its extensive therapeutic properties which may inhibit specific enzymes, blocking the angiotensin-converting enzyme (ACE) that raises blood pressure of infected patient during elevated fever clinical symptoms of SARS-CoV-2 (COVID-19). Spondias monbin extract may act by blocking the “suicide” enzyme cyclooxygenase that breaks down prostaglandins, they also prevent platelet aggregation. Cancer-battling antioxidants, flavonoids, have been found in relative abundance in Aframomum melegueta and Spondias mombin. Epicatechin have been proven to have diverse benefits to human health. It reduces the risks of diabetes mellitus and cardiovascular diseases, EGC acts as a strong inhibitor of HIV replication in cultured peripheral blood cells and inhibition of HIV-1 reverse transcriptase in vitro. EGC binds directly to CD4 molecules with consequent inhibition of Gp 120 binding and inactivate viruses in vitro by deformation of phospholipids, Epicatechin and other polyphenols decreases the susceptibility of low density lipoprotein to oxidation which prevents the initiation of artherosclerosis, HIV protein (Tat) and gp120.In conclusion. SARS-CoV-2(COVID-19) pandemic infection should not be a death sentence, it should be an advancement into the scientific world especially the naturally occurring product that can be used in the formulation of new antimicrobial agents.

Ubiquinol Ameliorates Endothelial Dysfunction in Subjects with Mild-to-Moderate Dyslipidemia: A Randomized Clinical Trial.

In this randomized, double-blind, single-center trial (ANZCTR number ACTRN12619000436178) we aimed to investigate changes in endothelium-dependent vasodilation induced by ubiquinol, the reduced form of coenzyme Q10 (CoQ10), in healthy subjects with moderate dyslipidemia. Fifty-one subjects with low-density lipoprotein (LDL) cholesterol levels of 130–200 mg/dL, not taking statins or other lipid lowering treatments, moderate (2.5%–6.0%) endothelial dysfunction as measured by flow-mediated dilation (FMD) of the brachial artery, and no clinical signs of cardiovascular disease were randomized to receive either ubiquinol (200 or 100 mg/day) or placebo for 8 weeks. The primary outcome measure was the effect of ubiquinol supplementation on FMD at the end of the study. Secondary outcomes included changes in FMD on week 4, changes in total and oxidized plasma CoQ10 on week 4 and week 8, and changes in serum nitrate and nitrite levels (NOx), and plasma LDL susceptibility to oxidation in vitro on week 8. Analysis of the data of the 48 participants who completed the study demonstrated a significantly increased FMD in both treated groups compared with the placebo group (200 mg/day, +1.28% ± 0.90%; 100 mg/day, +1.34% ± 1.44%; p < 0.001) and a marked increase in plasma CoQ10, either total (p < 0.001) and reduced (p < 0.001). Serum NOx increased significantly and dose-dependently in all treated subjects (p = 0.016), while LDL oxidation lag time improved significantly in those receiving 200 mg/day (p = 0.017). Ubiquinol significantly ameliorated dyslipidemia-related endothelial dysfunction. This effect was strongly related to increased nitric oxide bioavailability and was partly mediated by enhanced LDL antioxidant protection.

Antioxidant and Pro-Oxidant Properties of Carthamus Tinctorius, Hydroxy Safflor Yellow A, and Safflor Yellow A.

(1) Carthamus Tinctorius L. (safflower) is extensively used in traditional herbal medicine. (2) The aim of this study was to investigate the bioactive properties of polyphenol extracts from flowers of Carthamus Tinctorius (CT) cultivated in Italy. We also evaluated the properties of two bioactive water-soluble flavonoid compounds, hydroxy safflor yellow A (HSYA) and safflor yellow A (SYA), contained in Carthamus Tinctorius petals. (3) The total polyphenol content was 3.5 ± 0.2 g gallic acid equivalent (GAE)/100 g, flavonoids content was 330 ± 23 mg catechin equivalent (CE)/100 g in the flowers. The extract showed a high antioxidant activity evaluated by oxygen radical absorbance capacity (ORAC) and 2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging assays. In addition, flower extract, SYA, and HSYA were able to reduce the susceptibility of low-density lipoprotein to copper-induced lipid peroxidation. In order to investigate the bioactive properties of flower extract, SYA, and HSYA we also studied their modulatory effect of oxidative stress on human dermal fibroblasts (HuDe) oxidized by tert-butyl hydroperoxide (t-BOOH). The CT extract at concentrations ranging from 0.01–20 μg GAE/mL of polyphenols, exerted a protective effect against t-BOOH triggered oxidative stress. At higher concentration the extract exerted a pro-oxidant effect. Similar results have been obtained using HSYA and SYA. (4) These results demonstrate a biphasic effect exerted by HSYA, SYA, and flower extracts on oxidative stress.

Exogenous GM3 ganglioside inhibits atherosclerosis via multiple steps: A potential atheroprotective drug

Atherosclerosis is one of the leading causes of morbidity and mortality worldwide. A significant increase in ganglioside GM3 content generally happens in atherosclerotic plaques causing a GM3-enriched microenvironment. It remains unclear whether the GM3-enriched microenvironment influences atherogenesis. This study sought to answer the question by investigating exogenous GM3 effects on multiple steps involved in atherogenesis. First, the physicochemical properties of native low-density lipoprotein (LDL) and LDL enriched with exogenous GM3 (GM3-LDL) were characterized by dynamic laser scattering, atomic force microscopy, and agarose gel electrophoresis. Then, electrophoretic mobility, conjugated diene and malondialdehyde production, and amino group blockage of GM3-LDL/LDL were measured to determine LDL oxidation degrees and cellular recognition/internalization of GM3-LDL/GM3-oxLDL were detected via confocal microscopy and flow cytometry. Subsequently, influences of exogenous GM3 addition on the monocyte-adhering ability of endothelial cells and on lipid deposition in macrophages were investigated. Finally, exogenous GM3 effect on atherogenesis was evaluated using apoE−/− mice fed a high-fat diet. We found that exogenous GM3 addition increased the size, charge, and stability of LDL particles, reduced LDL susceptibility to oxidation and its cellular recognition/internalization, impaired the monocyte-adhering ability of endothelial cells and lipid deposition in macrophages. Moreover, exogenous GM3 treatment also significantly decreased blood lipid levels and atherosclerotic lesion areas in atherosclerotic mice. The data imply that exogenous GM3 had an inhibitory effect on atherogenesis, suggesting a protective role of a GM3-enriched microenvironment in atherosclerotic plaques and implying a possibility of exogenous GM3 as an anti-atherosclerotic drug.

Short-Term Bixin Supplementation of Healthy Subjects Decreases the Susceptibility of LDL to Cu2+-Induced Oxidation Ex Vivo.

Lycopene-based medications and supplements have been developed to prevent atherosclerosis, primarily because of their ability to decrease low-density lipoprotein (LDL) oxidation. Bixin and norbixin are carotenoids found in the seeds of annatto (Bixa orellana) and are colorants widely used by the food industry. Some studies have already demonstrated that these compounds have antioxidant and antiatherogenic potential in vitro and in animal models, but there is no evidence supporting the effects of their long-term or short-term consumption by humans. The aim of this study was to evaluate the effects of short-term intake of annatto carotenoids on biochemical and oxidative stress biomarkers as well as on the susceptibility of LDL oxidation in healthy individuals, using lycopene as a positive control. The effect of daily supplementation (0.05 mg/kg of body weight (b.w.)) with bixin, norbixin, lycopene, or placebo for 7 days was evaluated in a randomized, controlled crossover study in 16 healthy volunteers (8 men and 8 women). The susceptibility of LDL to Cu2+-induced oxidation ex vivo, biochemical parameters, and oxidative stress biomarkers were evaluated. No treatment affected biochemical parameters or most oxidative stress biomarkers. However, bixin reduced the oxidation rate of the LDL lipid moiety (−275%, p < 0.1) and nitric oxide metabolites (NOx) (−460%, p < 0.1), compared to the placebo group. Moreover, we observed that the changes in these parameters were positively associated, supporting the hypothesis that bixin decreases the susceptibility of LDL to Cu2+-induced oxidation by decreasing NOx levels, probably by downregulating the inducible nitric oxide synthase.

The Acute Effects of Cigarette Smoking on the Functional State of High Density Lipoprotein

BackgroundCigarette smoking disturbs plasma lipid level and lipoprotein metabolism; however, the effects of smoking on the functional state of high density lipoprotein (HDL) are still not clear. This study aimed to determine the antioxidant and antichemotactic properties of HDL and HDL-mediated cholesterol efflux in healthy subjects after cigarette smoking. Materials and MethodsHealthy male subjects, including nonsmokers (n = 16) and chronic smokers (n = 8), were enrolled. After smoking 8 cigarettes within 2 hours, plasma HDL was isolated and tested. Copper-induced low density lipoprotein (LDL) oxidation was used to determine the antioxidant ability of HDL. The concentration of serum amyloid A was measured by Enzyme Linked Immunosorbent Assay. Chemotaxis was detected by transwell assay. HDL-mediated cholesterol efflux was measured using fluorescent cholesterol analog. ResultsLDL baseline oxidation state was higher in chronic smokers than that in nonsmokers. Meanwhile, HDL-induced cholesterol efflux in macrophages in chronic smokers was significantly enhanced compared with that in nonsmokers. After acute smoking, both the antioxidant and antichemotactic ability of HDL declined in nonsmokers. However, in healthy chronic smokers, the effect of HDL on the susceptibility of LDL to oxidation was compensatorily enhanced. Nevertheless, their bodies were still in a higher oxidation state. Also, acute smoking did not affect HDL-mediated cholesterol efflux significantly in both nonsmokers and chronic smokers. ConclusionsOur data suggest that acute smoking attenuates the antioxidant and antichemotactic abilities of HDL in nonsmokers. Chronic smokers are in a higher oxidative state, although the antioxidant function of their HDL is compensatorily enhanced.

Association of socioeconomic stratification with plasmatic markers of lipoperoxidation and antioxidants in Venezuelan school-age children

To establish association between socioeconomic status and plasmatic markers of lipoperoxidation and antioxidants in Venezuelan school-age children from the middle-class and in critical poverty. Cross-sectional study with a sample of 114 school-age children (aged 7-9). The socioeconomic status, dietary intake of macro and micro-nutrients, weight, height, lipid profile, indicators of lipid peroxidation and enzymatic and non-enzymatic antioxidants were determined. The daily average intake of energy, carbohydrates and vitamin A, and the percentage of energy obtained from carbohydrates was significantly higher in middle-class children compared to critical poverty children (p <0.05). The circulating oxidized low density lipoprotein (p <0.001) and the susceptibility of low density lipoproteins and very low density lipoproteins to oxidation in vitro (p <0.05) were significantly higher in middle-class children, while the critical poverty children showed significantly lower levels of Vitamin C and E in plasma (p <0.05). Non-enzymatic antioxidant levels were frequently deficient in both strata. The concentrations of circulating oxidized low density lipoprotein (OR: 1.09, CI 95%: 1.016-1.179; p= 0.017) and Vitamin C (OR: 3.21, CI 95%: 1.104-9.938; p= 0.032) were associated to the socioeconomic status independently of gender, family history of premature coronary artery disease, triglicerides, Vitamin C and E dietary intake and count of white blood cells. The socioeconomic status was associated to circulating oxidized low density lipoprotein and Vitamin C in Venezuelan school-age children, The results suggested the need to improve the dietary intake of antioxidants in both studied socioeconomic groups.

Adiponectin: possible link between metabolic stress and oxidative stress in the elderly.

The aim of this study was to evaluate the relationships between the serum levels of adiponectin and systemic oxidative stress exerted on lipids, proteins, as well as endothelial function and cardiovascular diseases (CVD) risk markers, in elderly subjects with metabolic syndrome (MS). The serum advanced glycation and oxidation protein products, low-density lipoprotein susceptibility to oxidation (oxLDL), nitric oxide metabolic pathway products (NOx), serum lipid peroxidation, as well as total antioxidant/oxidative capacity (TAC/TOC), were analyzed in elderly subjects with MS (n=44), compared to aged-matched control (n=39). We pointed out significantly lower levels of adiponectin in elderly MS subjects concomitantly with significantly higher levels of oxidative stress and CVD risk markers. Significant positive correlations were found between serum adiponectin levels and HDL-cholesterol (p<0.05) and the total cholesterol/LDL-cholesterol ratio (p<0.01). Additionally, adiponectin levels were significantly inversely associated with insulin resistance index (HOMA-IR, r=-0.348; p<0.05) and serum lipid peroxidation (r=-0.337; p<0.05), and significantly positively with the antioxidant capacity (TAC, r=0.339; p<0.05). Conversely, adiponectin levels were significantly negatively (r=-0.310; p<0.05) associated with serum uric acid concentration. The major protective role of adiponectin versus stress related to an impaired glucose and lipid metabolism suggests that adiponectin plays a critical role in adiposity-related metabolic stress and redox homeostasis.

Effects of cyclodextrins on the structure of LDL and its susceptibility to copper-induced oxidation

Cyclodextrins (CDs) have long been widely used as drug/food carriers and were recently developed as drugs for the treatment of diseases (e.g. Niemann-Pick C1 and cancers). It is unknown whether cyclodextrins may influence the structure of low-density lipoprotein (LDL), its susceptibility to oxidation, and atherogenesis. In this study, four widely used cyclodextrins including α-CD, γ-CD, and two derivatives of β-CD (HPβCD and MβCD) were recruited. Interestingly, agarose gel electrophoresis (staining lipid and protein components of LDL with Sudan Black B and Coomassie brilliant blue, respectively but simultaneously) shows that cyclodextrins at relatively high concentrations caused disappearance of the LDL band and/or appearance of an additional protein-free lipid band, implying that cyclodextrins at relatively high concentrations can induce significant electrophoresis-detectable lipid depletion of LDL. Atomic force microscopy (AFM) detected that MβCD (as a representative of cyclodextrins) induced size decrease of LDL particles in a dose-dependent manner, further confirming the lipid depletion effects of cyclodextrins. Moreover, the data from agarose gel electrophoresis, conjugated diene formation, MDA production, and amino group blockage of copper-oxidized LDL show that cyclodextrins can impair LDL susceptibility to oxidation. It implies that cyclodextrins probably help to inhibit atherogenesis by lowering LDL oxidation.

Effects of lactic acid bacteria on low-density lipoprotein susceptibility to oxidation and aortic fatty lesion formation in hyperlipidemic hamsters.

We investigated the effects of Streptococcus thermophilus YIT 2001, a strain of lactic acid bacteria, on the susceptibility of low-density lipoprotein (LDL) to oxidation and the formation of aortic fatty lesions in hyperlipidemic hamsters. S. thermophilus YIT 2001 had the highest in vitro antioxidative activity against LDL oxidation among the 79 strains of lactic acid bacteria and bifidobacteria tested, which was about twice that of S. thermophilus YIT 2084. The lag time of LDL oxidation in the YIT 2001 feeding group was significantly longer than in controls, but was unchanged in the YIT 2084 group. After the feeding of YIT 2001, lag times were prolonged and areas of aortic fatty lesions were dose-dependently attenuated, although there were no effects on plasma lipid levels. These results suggest that YIT 2001 has the potential to prevent the formation of aortic fatty lesions by inhibiting LDL oxidation.

Pine bark extract prevents low-density lipoprotein oxidation and regulates monocytic expression of antioxidant enzymes

Polyphenols are widely distributed in leaves, seeds, bark, and flowers and considered to have beneficial effects on cardiovascular health. We hypothesized that the potent antioxidant properties of pine bark extract (PBE) are exerted by its ability to scavenge free radicals and induce antioxidant enzymes. Therefore, we investigated the effects of PBE on low-density lipoprotein (LDL) oxidation and the antioxidant defense system in monocytes. Oxidative susceptibility of LDL was determined by lag time assay in vitro and by using a human umbilical vein endothelial cell–mediated oxidation model. THP-1 monocytic cells were treated with PBE, and the expression of antioxidant enzymes was measured by real-time polymerase chain reaction and Western blot. Pine bark extract showed radical scavenging ability and significantly inhibited free radical-induced and endothelial cell-mediated LDL oxidation in vitro. Pine bark extract treatment resulted in increases in the expressions of antioxidant enzymes, glutathione peroxidase-1, catalase, and heme oxygenase-1 in THP-1 cells. In addition, PBE induced nuclear factor-erythroid-2–related factor 2 activation, which was accompanied by the activation of extracellular signal-regulated kinase and Akt despite a down-regulation of reactive oxygen species. After the monocyte investigations, we further examined the antioxidant effect after the intake of PBE by 10 healthy male volunteers. Pine bark extract significantly prolonged the lag time of LDL oxidation. Based on our findings, it appears that PBE enhances the antioxidant defense capacity of LDL and monocytes and may play a preventive role in atherosclerosis progression.

Plasma paraoxonase 1 arylesterase activity in d-galactose-induced aged rat model: correlation with LDL oxidation and redox status

There is much evidence linking the involvement of oxidative stress in the pathogenesis of aging. Paraoxonase 1 (PON1) is an HDL-associated antioxidant enzyme that inhibits the oxidative modification of low-density lipoproteins (LDL). We have investigated the changes in plasma PON1 activity, LDL oxidation, radical scavenging activity and lipid peroxidation in D-galactose-induced aging rat model and also compared the results with 24-month naturally aged rats. Arylesterase activity of PON1, susceptibility of LDL for oxidation, plasma radical scavenging activity and plasma thiobarbituric acid reactive substances (TBARS) were measured in normal control rats (4-months-old control rats subjected to D-galactose-induced experimental aging, and 24-month-old naturally aged rats). There was a significant decrease in plasma PON1 arylesterase activity in both subcutaneous D-galactose-treated groups and 24-month-old aged rats (P < 0.05, for each). TBARS, an oxidative stress marker, was seen to increase in the experimental groups (P < 0.01). In both subcutaneous galactose-treated and naturally aged rats, there was a significant rise in plasma LDL oxidation (P < 0.05, for each). However, radical scavenging activity was decreased significantly (P < 0.01) in both groups, as compared to control. The D-galactose-induced rat model of aging mimics the naturally aged rat with reference to PON1 arylesterase activity and susceptibility to LDL oxidation. The results emphasize the importance of PON1 with respect to aging and its association with redox balance of the body.

Onion extract (Allium cepa L.) up-regulates paraoxonase 1 activity with concomitant protection against LDL oxidation in male wistar strain rats subjected to mercuric chloride induced oxidative stress

Onion (Allium cepa L.) is one of the rich sources of flavonoids, consisting mainly of the major flavonols quercetin-3,4'-O-diglucoside (QDG) and quercetin-4'-O-monoglucoside (QMG) with high therapeutic properties. Paraoxonase1 (PON1) protects the oxidative modification of low density lipoprotein (LDL) and is a major anti-atherosclerotic protein component of high-density lipoprotein (HDL). We explored the roles of onion extracts and flavonoids (quercetin & catechin) in the regulation of PON1 expression by measuring its arylesterase activity and correlating with plasma MDA and oxidized LDL levels, as a marker of oxidative stress in wistar strain rats subjected to mercuric chloride (HgCl2) induced oxidative insult. Rats were divided into eight groups. Control, Experimental (HgCl2 treated), Exp + onion extract/catechin/quercetin, Positive control (Normal + onion/catechin/quercetin). Treatment continued for 4 weeks. PON1 activity decreased in rats treated with HgCl2 (HgCl2 treated 23.83 U/ml plasma; control value: 33.20 U/ml plasma) with an increase in susceptibility of LDL for oxidation (values derived after 3000 s; Pearson's r = 0.9970, p< 0.001; control value: Pearson's r = 0.9980, p< 0.001) and plasma MDA level (0.408 nmol/ml plasma; control value: 0.202 nmol/ml plasma). Onion extracts successfully and significantly attenuated the adverse effects of HgCl2 by up regulating PON1 activity (28.10 U/ml plasma) and its protective capacity against LDL oxidation (Pearson's r = 0.9978, p< 0.001) and lipid peroxidation (0.313 nmol/ml plasma). Similar effects were shown by quercetin and catechin with improved oxidative status either by enhancing PON1activities (31.36 & 24.76 U/ml plasma) and antioxidant defenses (0.24 & 0.28 nmol/ml plasma MDA level) or reducing susceptibility to LDL oxidation (Pearson's r = 0.9973 & 0.9984, p < 0.001), when given to oxidatively stressed rats.

Advanced oxidative and glycoxidative protein damage markers in the elderly with type 2 diabetes

We aimed to explore the association of advanced oxidation and advanced glycation of proteins, and their interrelations with endothelial nitric oxide synthesis, oxidative stress, metabolic profile as well as other atherosclerotic risk markers in prediabetic and diabetic elderly subjects. Advanced glycation end products (AGEs), advanced oxidation protein products (AOPPs), low-density lipoprotein susceptibility to oxidation (oxLDL) and nitric oxide metabolic pathway products (NOx) were assessed in subjects with impaired fasting glucose (prediabetes, IFG; n=90), and type 2 diabetes mellitus (T2DM, n=95) versus control subjects (n=88). Higher levels of AOPPs, AGEs, oxLDL, NOx, atherosclerosis risk markers, and insulin resistance were pointed out in IFG and T2DM groups compared with control. Strong positive associations (p<0.01) of AGEs with fasting glucose and HbA1c were found in both hyperglycemic groups, whereas AOPPs were significantly correlated (p<0.01) only in T2DM. In T2DM, AGEs and AOPPs significantly (p<0.01) correlated with insulin resistance index HOMA-IR, oxLDL and small LDL particle size (TG/HDL-C), and positively with NOx. Direct associations of AGEs and AOPPs with TC/HDL-C and oxLDL/HDL-C, and AGEs-AOPPs interrelations (p<0.01) were identified in IFG and T2DM groups. AGEs and AOPPs in combination with oxLDL and NOx could be important biomarkers for evaluating the association between diabetes and atherosclerotic disorders in aging diabetic patients. In the present study we have made an attempt to approach the biological and clinical significance of the oxidative and glycoxidative protein damage, in subjects with prediabetes and type-2 diabetes mellitus. AGEs and AOPPs in combination with oxLDL and NOx appear to be important biomarkers for evaluating the association between diabetes and atherosclerotic disorders in aging diabetic patients. More importantly, this cluster of biomarkers that links the short term, "real time" metabolic impairment parameters (NOx, serum glucose, HOMA-IR, serum lipid profile) and the "metabolic memory" markers resulting from the long-term hyperglycemia and hyperlipidemia-induced oxidative stress (HbA1c, AGEs, AOPPs and oxLDL), could be valuable in predicting not only vascular complications in T2DM, but also the onset of diabetes, hence enabling therapeutic interventions from the early stages of diabetes. This article is part of a Special Issue entitled: Posttranslational Protein modifications in biology and Medicine.