The Effect of Statins on the Differentiation and Function of Central Nervous System Cells.

Statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) reduce plasma cholesterol and improve endothelium-dependent vasodilation, inflammation, and oxidative stress. The effect of statins on the central nervous system (CNS), particularly on cognition and neurological disorders such as cerebral ischemic stroke, multiple sclerosis (MS), and Alzheimer's disease (AD), has received increasing attention in recent years, both within the scientific community and in the media. This review aims to provide an updated discussion on the effects of statins on the differentiation and function of various nervous system cells, including neurons and glial cells. Additionally, the mechanisms of action and how different types of statins enter the CNS will be discussed.

Marine Chitosan-Oligosaccharide Ameliorated Plasma Cholesterol in Hypercholesterolemic Hamsters by Modifying the Gut Microflora, Bile Acids, and Short-Chain Fatty Acids.

This study evaluated the cholesterol-alleviating effect and underlying mechanisms of chitosan-oligosaccharide (COS) in hypercholesterolemic hamsters. Male hamsters (n = 24) were divided into three groups in a random fashion, and each group was fed one particular diet, namely a non-cholesterol diet (NCD), a high-cholesterol diet (HCD), and an HCD diet substituting 5% of the COS diet for six weeks. Subsequently, alterations in fecal bile acids (BAs), short-chain fatty acids (SCFAs), and gut microflora (GM) were investigated. COS intervention significantly reduced and increased the plasma total cholesterol (TC) and high-density lipoprotein-cholesterol (HDL-C) levels in hypercholesteremic hamsters. Furthermore, Non-HDL-C and total triacylglycerols (TG) levels were also reduced by COS supplementation. Additionally, COS could reduce and increase food intake and fecal SCFAs (acetate), respectively. Moreover, COS had beneficial effects on levels of BAs and GM related to cholesterol metabolism. This study provides novel evidence for the cholesterol-lowering activity of COS.

Is There a Correlation between Dietary and Blood Cholesterol? Evidence from Epidemiological Data and Clinical Interventions.

Dietary cholesterol has been a topic of debate since the 1960s when the first dietary guidelines that limited cholesterol intake to no more than 300 mg/day were set. These recommendations were followed for several years, and it was not until the late 1990s when they were finally challenged by the newer information derived from epidemiological studies and meta-analysis, which confirmed the lack of correlation between dietary and blood cholesterol. Further, dietary interventions in which challenges of cholesterol intake were evaluated in diverse populations not only confirmed these findings but also reported beneficial effects on plasma lipoprotein subfractions and size as well as increases in HDL cholesterol and in the functionality of HDL. In this review, we evaluate the evidence from recent epidemiological analysis and meta-analysis as well as clinical trials to have a better understanding of the lack of correlation between dietary and blood cholesterol.

A Less than Provocative Approach for the Primary Prevention of CAD.

Coronary artery disease (CAD) risk increases in proportion to the magnitude and duration of exposure to plasma low-density lipoprotein cholesterol (LDL-C), doubling every additional decade of exposure. Early primary prevention is three times more effective than initiated later. Several clinical trials show plasma LDL-C of 15-40 mg/dL is more effective and equally safe as the Current Cardiovascular Clinical Practice Guidelines (CCCPG) recommended target of 70mg/dL. The cholesterol in the blood is the excess synthesized by the cells and secreted into the blood for disposal in the liver. The CCCPG is inadequate since traditional risk factors (TRF) are not detectable until the sixth and seventh decade. The genetic risk score (GRS) evaluated in 1 million individuals as a risk stratifier for CAD is superior to TRF. Genetic risk for CAD was reduced by 30-50% by statin therapy, PCSK9 inhibitors, and lifestyle changes. The GRS does not change during one's lifetime and is inexpensive. Incorporating genetic risk stratification into CCCPG would induce a paradigm shift in the primary prevention of CAD.

Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and "Missing" Heritability.

Changes in plasma low-density lipoprotein cholesterol (LDL-c) levels relate to a high risk of developing some common and complex diseases. LDL-c, as a quantitative trait, is multifactorial and depends on both genetic and environmental factors. In the pregenomic age, targeted genes were used to detect genetic factors in both hyper- and hypolipidemias, but this approach only explained extreme cases in the population distribution. Subsequently, the genetic basis of the less severe and most common dyslipidemias remained unknown. In the genomic age, performing whole-exome sequencing in families with extreme plasma LDL-c values identified some new candidate genes, but it is unlikely that such genes can explain the majority of inexplicable cases. Genome-wide association studies (GWASs) have identified several single-nucleotide variants (SNVs) associated with plasma LDL-c, introducing the idea of a polygenic origin. Polygenic risk scores (PRSs), including LDL-c-raising alleles, were developed to measure the contribution of the accumulation of small-effect variants to plasma LDL-c. This paper discusses other possibilities for unexplained dyslipidemias associated with LDL-c, such as mosaicism, maternal effect, and induced epigenetic changes. Future studies should consider gene-gene and gene-environment interactions and the development of integrated information about disease-driving networks, including phenotypes, genotypes, transcription, proteins, metabolites, and epigenetics.

Choline Intake as Supplement or as a Component of Eggs Increases Plasma Choline and Reduces Interleukin-6 without Modifying Plasma Cholesterol in Participants with Metabolic Syndrome.

Metabolic syndrome (MetS) is characterized by low-grade inflammation and insulin resistance, which increase the risk of heart disease. Eggs have numerous nutrients including choline, carotenoids, and fat-soluble vitamins that may protect against these conditions. Egg phosphatidylcholine (PC) is a major contributor of dietary choline in the American diet. However, uncertainty remains regarding eggs due to their high concentration of cholesterol. In this study, we evaluated the effect of two sources of choline, whole eggs (a source of PC) and a choline supplement (choline bitartrate, CB), on plasma lipids, glucose, insulin resistance, and inflammatory biomarkers. We recruited 23 subjects with MetS to participate in this randomized cross-over intervention. After a 2-week washout, with no choline intake, participants were randomly allocated to consume three eggs/day or CB (~400 mg choline/d for both) for 4 weeks. After a 3-week washout period, they were allocated to the alternate treatment. Dietary records indicated higher concentrations of vitamin E and selenium during the egg period (p < 0.01). Interestingly, there were no changes in plasma total, low density lipoprotein (LDL)- or high density lipoprotein (HDL)-cholesterol, triglycerides, or glucose, compared either to baseline or between treatments. In contrast, interleukin-6 was reduced, with both sources of choline compared to baseline, while eggs also had an effect on lowering C-reactive protein, insulin, and insulin resistance compared to baseline. This study demonstrates that in a MetS population, intake of three eggs per day does not increase plasma LDL cholesterol, and has additional benefits on biomarkers of disease compared to a choline supplement, possibly due to the presence of other antioxidants in eggs.

Erythroleukemia treated effects of rat plasma profile and erythrocyte membranes.

Erythroleukemia disease is caused by over production of malignant blood and immature large number of blood cells enters into peripheral compartment. Biophysical and biochemical changes in plasma and erythrocyte membrane in erythroleukemia treated rats were identified. Our study, leukemia is experimentally exposed in rats were injecting erythroleukemia cells (FLC) (H-2d) intravenously in adult rats and normal control rats were maintained. Significant increase in the activity of blood glucose, proteins levels, aspartate transaminase (AST) and alanine transaminase (ALT) values and significant decrease in haemoglobin (Hb), albumin levels in erythroleukemia treated rats were observed when compared with control rats. Cholesterol and low density liproprotein (LDL) levels increased significantly in erythroleukemia treated rats but triglycerides, high density lipoprotein (HDL) and very low density lipoprotein (VLDL) levels decreased significantly. Levels of red cell membrane cholesterol decreased in erythroleukemia treated rats in comparison with control while levels of phospholipids and proteins increased in erythrocytes of erythroleukemia treated rats. Red blood cell (RBC) and white blood cell (WBC) counts increased significantly and platelet count decreased. C/P (cholesterol/phospholipid) ratio decreased significantly in erythroleukemia treated rats. This study has been undertaken for the first time to investigate the effect of (FLC) (H-2d) erythroleukemia cells (treated) in intravenously in adult rats and normal control rats. Results indicate biophysical and biochemical alterations at molecular level in plasma and erythrocyte membrane.

Two weeks of western diet disrupts liver molecular markers of cholesterol metabolism in rats.

BACKGROUND: The present study was designed to test the hypothesis that in the liver, excessive fat accumulation impairs cholesterol metabolism mainly by altering the low-density lipoprotein-receptor (LDL-R) pathway. METHOD: Young male Wistar rats were fed standard (SD), high fat (HFD; 60% kcal) or Western (WD; 40% fat + 35% sucrose (17.5% fructose)) diets for 2 or 6 weeks. RESULTS: Weight gain (~ 40 g) was observed only following 6 weeks of the obesogenic diets (P < 0.01). Compared to the 2-week treatment, obesogenic diets tripled fat pad weight (~ 20 vs 7 g) after 6 weeks. Hepatic triglyceride (TG) levels were greater in response to both the WD and HFD compared to the SD (P < 0.01) at 2 and 6 weeks and their concentrations were greater (P < 0.05) in WD than HFD at 2 weeks. Plasma total cholesterol levels were higher (P < 0.05) in animals submitted to WD. After 2 and 6 weeks, liver expression of LDL-R, proprotein convertase subtilisin/kexin 9 (PCSKk9) and sterol regulatory element binding protein 2 (SREBP2), involved in LDL-cholesterol uptake, was lower in animals submitted to WD than in others treated with HFD or SD (P < 0.01). Similarly, low-density lipoprotein-receptor-related protein 1 (LRP1) and acyl-CoA cholesterol acyltransferase-2 (ACAT-2) mRNA levels were lower (P < 0.01) among WD compared to SD-fed rats. Expression of the gene coding the main regulator of endogenous cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) was reduced in response to WD compared to SD and HFD at 2 (P < 0.001) and 6 (P < 0.05) weeks. Being enriched in fructose, the WD strongly promoted the expression of carbohydrate-response element binding protein (ChREBP) and acetyl-CoA carboxylase (ACC), two key regulators of de novo lipogenesis. CONCLUSION: These results show that the WD promptly increased TG levels in the liver by potentiating fat storage. This impaired the pathway of hepatic cholesterol uptake via the LDL-R axis, promoting a rapid increase in plasma total cholesterol levels. These results indicate that liver fat content is a factor involved in the regulation of plasma cholesterol.

Hypercholesterolemia Accelerates Both the Initiation and Progression of Angiotensin II-induced Abdominal Aortic Aneurysms.

OBJECTIVE: This study determined whether hypercholesterolemia would contribute to both the initiation and progression of angiotensin (Ang)II-induced abdominal aortic aneurysms (AAAs) in mice. METHODS AND RESULTS: To determine whether hypercholesterolemia accelerates the initiation of AAAs, male low-density lipoprotein (LDL) receptor -/- mice were either fed one week of Western diet prior to starting AngII infusion or initiated Western diet one week after starting AngII infusion. During the first week of AngII infusion, mice fed normal diet had less luminal expansion of the suprarenal aorta compared to those initiated Western diet after the first week of AngII infusion. The two groups achieved comparable luminal dilation on week 2 through week 6 of AngII infusion as monitored by ultrasound. To determine whether hypercholesterolemia contributed to the progression of established AAAs, male LDL receptor -/- mice were fed Western diet and infused with AngII for 4 weeks. Mice with established AAAs were then stratified into two groups based on luminal diameters measured by ultrasound. While AngII infusion was continued for another 8 weeks in both groups, mice in one group were continuously fed Western diet, but diet in the other group was switched to normal laboratory diet. In the latter group, plasma cholesterol concentrations were reduced rapidly to approximately 500 mg/dl within one week after the diet was switched from Western diet to normal laboratory diet. Luminal expansion progressed constantly in mice continuously fed Western diet, whereas no continuous expansion was detected in mice that were switched to normal laboratory diet. CONCLUSION: Hypercholesterolemia accelerates both the initiation of AAAs and progression of established AAAs in AngII-infused male LDL receptor -/- mice. CLINICAL RELEVANCE: Hypercholesterolemia is modestly associated with AAAs in observational or retrospective clinical studies. It is not feasible to study whether hypercholesterolemia contributes to the initiation of AAAs or progression of established AAAs in human. This study using AngII-induced AAA mouse model provides solid evidence that hypercholesterolemia contributes to both the initiation and progression of AAAs, supporting that statin therapy at any stage of AAA development may be beneficial to hypercholesterolemic patients with AAAs.

Plasma Cholesterol-Lowering Activity of Soybean Germ Phytosterols.

Soybean germ phytosterols (SGP) largely exist in soybean germ oil. Our previous study demonstrated that soybean germ oil was effective in reducing plasma cholesterol. However, it remains unknown if its phytosterols are the active ingredients responsible for the plasma cholesterol-lowering activity. The present study aimed to test the effect of SGP on plasma cholesterol and to investigate its associated underlying mechanisms using hamsters as animal model. Male hamsters (n = 40) were randomly divided into five groups (n = 8/group) and fed one of the five diets: a non-cholesterol diet (NCD), a high cholesterol diet (HCD), a HCD diet containing 0.5% cholestyramine (PC), and two HCD diets containing 0.1% (LP) and 0.2% (HP) SGP, respectively, for six weeks. Results showed that SPG reduced plasma cholesterol level in a dose-dependent manner, whereas it dose-dependently increased the excretion of both fecal neutral and acidic sterols. SGP was also effective in displacing cholesterol from micelles. It was concluded that SGP possessed hypocholesterolemic activity, likely by inhibiting cholesterol absorption in the intestine and promoting fecal sterol excretion.

FADS and PPARG2 Single Nucleotide Polymorphisms are Associated with Plasma Lipids in 9-Mo-Old Infants.

BACKGROUND: Dietary intake of polyunsaturated fatty acids (PUFAs), e.g., linoleic acid and n-3 (ω-3) long-chain PUFAs, has been shown in adults to affect plasma cholesterol and triglycerides (TGs), respectively. Little is known about the effects of PUFAs on plasma lipids in early life. OBJECTIVE: The aim of this study was to explore the associations between plasma concentrations of total, LDL, and HDL cholesterol and TGs in infants and 2 single nucleotide polymorphisms (SNPs) in the fatty acid desaturase genes (FADS) oppositely associated with docosahexaenoic acid (rs1535 and rs174448) and potential effect modification by a functional peroxisome proliferator-activated receptor-γ2 gene variant (PPARG2 Pro12Ala). METHODS: In 9-mo-old infants (n = 561) from 3 Danish cohorts, we analyzed associations between plasma lipids, erythrocyte PUFAs, and FADS SNPs, and interactions with PPARG2 Pro12Ala genotype, by multiple linear regression. We also examined potential effect modification by breastfeeding, as 46% of the infants were still being breastfed. RESULTS: Minor allele carriage of rs174448 was associated with lower total cholesterol (difference: -0.22 mmol/L; 95% CI: -0.37, -0.06 mmol/L; P = 0.006) and LDL cholesterol (difference: -0.15 mmol/L; 95% CI: -0.29, -0.01 mmol/L; P = 0.035), but no associations were observed with TGs or for rs1535. Minor allele carriage of both FADS SNPs was associated with 1 SD lower HDL cholesterol, but only in currently breastfed infants (rs174448 × breastfeeding, P = 0.080; rs1535 × breastfeeding, P = 0.030) and PPARG2 minor allele carriers (rs174448 × PPARG2, P = 0.001; rs1535 × PPARG2, P = 0.004). Erythrocyte arachidonic acid and eicosapentaenoic acid were inversely associated with LDL cholesterol [estimated effect (ß): -0.3 mmol/L; 95% CI: -0.06, -0.00 mmol/L per percentage of fatty acids (FA%); P = 0.035] and TGs (ß: -0.23 mmol/L; 95% CI: -0.41, -0.05 mmol/L per FA%; P = 0.015), respectively. CONCLUSIONS: The observed associations with FADS variants indicate that PUFAs are involved in plasma lipid regulation in 9-mo-old infants. Observed FADS SNP differences and interactions with breastfeeding and PPARG2 warrant additional studies to explore the effects of individual FADS SNPs on PUFA status and potential genetic modification of dietary PUFA effects.

Hypocholesterolemic Effect of the Lignin-Rich Insoluble Residue of Brewer's Spent Grain in Mice Fed a High-Fat Diet.

Insoluble residue (INS) is a lignin-rich fraction of brewer's spent grain (BSG) that also contains ß-glucan and arabinoxylan, the major constituents of dietary fiber. We investigated the effects of INS in diet-induced obese mice in terms of lipid metabolism and metabolic diseases. Male mice (C57bl6) were fed a high-fat diet (HFD), a HFD + 20% INS, a HFD + 20% cellulose (CEL), a HFD with a combination of 20% INS-CEL (1:1), or a control diet for 14 weeks. Insulin and glucose tolerance tests were performed after 12 weeks. Fasting plasma lipids, bile acid, and fecal bile acid were measured after 14 weeks of feeding, and tissues were collected for gene expression analysis. Body weight gain was significantly reduced with all fibers, but only INS and INS-CEL decreased fasting plasma low-density lipoprotein cholesterol and total cholesterol compared to HFD. CEL and INS-CEL significantly improved insulin resistance. Fecal bile acids were significantly increased by all fibers, but there was no change in plasma bile acid. Clostridium leptum was increased with all fibers, but universal bacterial diversity was only with INS and INS-CEL. In addition, INS significantly increased the abundance of Bacteriodes, while CEL decreased Atopobium and Lactobacillus. INS feeding significantly upregulated various genes of cholesterol and bile acid metabolism, such as Srebp2, Hmgcr, Ldlr, Cyp7a1, Pparα, Fxr, and Pxr, in the liver. INS, INS-CEL, and CEL significantly attenuated liver steatosis. Our results suggest that INS from BSG induced beneficial systemic changes in mice via gut microbiota, bile acids, and gene expression in the liver.

Low cholesterol is not always good: low cholesterol levels are associated with decreased serotonin and increased aggression in fish.

The inverse relationship between serum cholesterol and levels of aggression led to the cholesterol-serotonin hypothesis. According to this hypothesis, low dietary cholesterol intake leads to depressed central serotonergic activity, which is associated with increased aggression. Here we present the hypothesis about the evolutionary origins of low cholesterol and aggressive behavior, investigating the relationship between low levels of plasma cholesterol and aggressive behavior in fish. We used Nile tilapia (Oreochromis niloticus), a species of aggressive fish with a clear dominant subordinate relation, as an experimental model. The fish were treated with statin, a cholesterol-lowering drug. Aggressive behavior, brain serotonin (5-HT) concentrations, 5-hydroxyindoleacetic acid (5-HIAA, the major 5-HT metabolite) and plasma cholesterol were analyzed after chronic administration of statin. Our results show that fish treated with statin exhibited reduced plasma cholesterol, reduced telencephalic indexes of 5-HIAA/5-HT and increased aggressive behavior compared to control fish. These results indicate that changes in plasma cholesterol may affect neurochemical processes underlying aggressive behavior in fish, suggesting an evolutionary mechanism conserved among vertebrates. Such mechanisms may be important for the control of aggression in many vertebrate species, not just mammals, as has been demonstrated so far.

Dose-Dependent Increases in Liver Cholesterol but Not Plasma Cholesterol from Consumption of One to Five Whole Eggs and No Effects from Egg Whites on Liver or Plasma Cholesterol in Hamsters.

The dose-dependent effect of egg consumption on plasma cholesterol in humans remains inconclusive. It is unknown if egg white consumed in a normal amount can reduce plasma cholesterol. We used hamsters as a model to (i) investigate the dose-dependent effect of consuming zero to five whole eggs on plasma total cholesterol (TC) and (ii) examine if egg white, equivalent to one to five eggs, possessed any reducing effects on plasma TC. In experiment 1, hamsters were divided into six groups ( n = 8 each) and fed either a control diet or one of five experimental diets supplemented with whole-egg powder equivalent to one to five eggs per 2000 kcal. Results showed that supplementation with one egg increased plasma TC by 25% compared with that of the control (226 ± 16 versus 282 ± 56 mg/dL, p < 0.05), whereas supplementation with two to five eggs did not significantly produce any additional effects on plasma cholesterol. However, supplementation with one to five eggs in diets caused a dose-dependent accumulation of cholesterol in the liver from 21.5 ± 4.4 to 71.3 ± 7.3 mg/g ( p < 0.01). In the second experiment, hamsters were divided into six groups and fed either a high-cholesterol control diet or one of five experimental diets supplemented with egg-white powder from one to five eggs. Results showed that egg-white powder affected neither plasma nor liver cholesterol levels. The egg-white powder did not affect fecal sterol excretion, suggesting it had no effect on cholesterol absorption. It was therefore concluded that consumption of two to five eggs did not significantly produce any additional effects on plasma cholesterol, whereas egg white did not possess a plasma-cholesterol-lowering activity if it was consumed at amounts similar to those in a normal human diet.

Bacterial Fermentation of Water-Soluble Cellulose Acetate Raises Large-Bowel Acetate and Propionate and Decreases Plasma Cholesterol Concentrations in Rats.

We hypothesized that water-soluble cellulose acetate (WSCA) could be useful tool for the delivery of short-chain fatty acids to the large intestine. Rats were fed a control diet or a diet containing graded levels of WSCA for up to 21 days. Consuming WSCA dose-dependently increased large-bowel acetate and propionate concentrations through the bacterial fermentation. When WSCA was used as substrate, acetyl esterase activity in the cecal bacteria was detected solely in rats fed WSCA, in which the activity increased over time accompanied by an increased number of Bacteroides xylanisolvens. Consuming WSCA at a 4% level increased the goblet cell numbers and mucin contents in the cecum and lowered plasma cholesterol concentrations, which tended to correlate with the portal plasma concentrations of propionate. The results suggest that bacterial fermentation of WSCA is characterized by the greater production of acetate and propionate, which may contribute to the physiologic alterations.

Cupremia y colesterolemia como factores de riesgo en pacientes con enfermedad de Alzheimer / Plasma levels of copper and cholesterol as risk factors in Alzheimer disease patients / Cupremia e colesterolemia como fatores de risco em pacientes com doença de Alzheimer

Se estudiaron 241 personas, 119 controles y 122 pacientes con enfermedad de Alzheimer (EA) subagrupados en tres categorías de acuerdo con el estadio clínico de la dolencia, con el objetivo de investigar la influencia de niveles elevados de cobre libre y colesterol plasmático como factores de riesgo para la EA. Las conclusiones obtenidas de los resultados indicaron que los pacientes expuestos a una combinación de alto colesterol y de cobre no unido a ceruloplasmina tuvieron mayor proporción de marcadores de estrés oxidativo (carbonilos proteicos, sustancias reactivas al tiobarbiturato, glutatión oxidado y descenso de antioxidantes totales en sangre), conjuntamente con un incremento de HDL-colesterol peroxidado y lipoproteína "a" que correlacionó con la gravedad de su cuadro. Lo mismo sucedió con la relación entre péptidos amiloides (1-40) y (1-42) en plasma y los valores del mini-test de estado cognitivo (MMSE). Se halló que una función de adición de efectos que cuantificó el daño por cobre libre y colesterol oxidado resultó directamente proporcional a la pérdida de desempeño cognitivo estimada por medio del MMSE. Esta función es de fácil determinación y puede considerarse un nuevo biomarcador para estudiar riesgo en poblaciones expuestas, apoyar el diagnóstico clínico, o evaluar la eficacia de estrategias terapéuticas en pacientes con EA.

Alzheimer disease (AD) patients (122) compared to control subjects (119) were studied to determine the role of chronic exposure of hypercholesterolemic plasma levels and free copper (not bound to ceruloplasmin) as biomarkers of progression for AD. Oxidative stress parameters, lipid profile, amyloid levels, and cognitive status were studied in all participants. Conclusions obtained indicated that patients exposed simultaneously to free copper and increased cholesterol levels present higher indicators of oxidative stress (protein carbonyls, thiobarbituric acid-reactive substances, decreased total antioxidant activity in plasma and elevated oxidized HDL-cholesterol). Lipoprotein "a" concentrations also correlated with the clinical progression of the disease. The ratio amyloid ß(1-40)/ß(1-42) in plasma inversely correlated with the cognitive performance estimated by the Mini-Mental State Examination Test (MMSE). A defined function that weighs the contribution of the deleterious effect produced by combined free copper and Ox-HDL-cholesterol exposure directly correlated with the loss of cognitive performance. Thus, this biomarker could be a new tool for the screening of large populations under risk, or may be a useful way to estimate the efficacy of therapeuti approaches in patients suffering AD.

Foram estudadas 241 pessoas, 119 controles e 122 pacientes com doença de Alzheimer (DA), agrupados em três categorias de acordo com o estágio clínico da doença, com o objetivo de investigar a influência de níveis elevados de cobre livre e colesterol plasmático como fatores de risco para a DA. As conclusões obtidas a partir dos resultados indicaram que os pacientes expostos a uma combinação de colesterol alto e de cobre não ligados à ceruloplasmina apresentaram maior proporção de marcadores de estresse oxidativo (carbonilos proteicos, substâncias reativas ao tiobarbiturato, glutationa oxidada e diminuição dos antioxidantes totais no sangue ), juntamente com um aumento da HDL-colesterol peroxidado e lipoproteína "a" que correlacionou com a gravidade de sua condição. O mesmo aconteceu com a relação entre os peptídeos amilóides (1-40) e (1-42) em plasma e os valores do mini-teste do estado cognitivo (MMSE). Verificou-se que uma função de adição de efeitos que quantificou o dano por cobre livre e colesterol oxidado resultou diretamente proporcional à perda de desempenho cognitivo estimada através do MMSE. Esta função é fácil de determinar e pode ser considerada um novo biomarcador para estudar o risco em populações expostas, apoiar o diagnóstico clínico ou avaliar a eficácia de estratégias terapêuticas em pacientes com DA.

Soybean amplifies the hypohomocysteinemic effect of betaine and improves its hypercholesterolemic effect.

We examined whether soybean (SB) and soy protein isolate (SPI) can prevent the betaine-induced elevation of plasma cholesterol as well as maintain the betaine-induced reduction of plasma Hcy concentration. Rats were fed casein-, SB-, or SPI-based diet with or without betaine; SPI-based diet with betaine containing soybean fiber (SF) or soy lecithin (SL) or the combination of SF and SL. Plasma Hcy concentration was decreased by feeding betaine to rats fed the casein-, SB-, and SPI-based diets. Betaine-induced elevation of plasma cholesterol was decreased by feeding the SB-based diet compared with the casein-based diet, but was not decreased by feeding the SPI-based diet. In rats fed the SPI-based diet, the increased concentration of plasma cholesterol by betaine feeding was not prevented by independent addition of SL or SF, but was prevented by a combination of SL and SF, and was associated with increased fecal excretion of bile acids.

Risk of Late-Onset Alzheimer's Disease by Plasma Cholesterol: Rational In Silico Drug Investigation of Pyrrole-Based HMG-CoA Reductase Inhibitors.

Alzheimer's disease (AD), a worldwide renowned progressive neurodegenerative disorder, is the most common cause of dementia. There are several studies on the important role of cholesterol metabolism in AD pathogenesis, which indicated that the high concentrations of serum cholesterol increase the risk of AD. Biosynthesis of the plasma cholesterol and other isoprenoids is catalyzed by 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) through the conversion of HMG-CoA to mevalonic acid in mevalonate pathway. Normally, the high level of plasma cholesterol is downregulated by HGMCR inhibition as the result of degradation of LDL, but in abnormal conditions, for example, high blood glucose, the HMGCR over activated resulting in uncontrolled blood cholesterol. Selective HMGCR inhibitor drugs such as statins, which increase the catabolism of plasma LDL and reduce the plasma concentration of cholesterol, have been investigated as a possible treatment for AD. In the present study, we have identified the binding modes of 22 various derivatives of 3-sulfamoylpyrroles 16, prepared via a [3 + 2] cycloaddition of a münchnone with a sulfonamide-substituted alkyne, by using efficient biocomputational tools. Out of 22, 5 ligands, with code numbers 5b, 5c, 5d, 5i, and 5j, possessed most absorption, distribution, metabolism, and excretion (ADME) and toxicity profiles in acceptable ranges. Among ligands, 5j (sodium (3R,5R)-7-(3-(N,N-dimethylsulfamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate) could inhibit HMGCR enzyme in inhibitory binding site with affinity value -12.17 kcal/mol and binding energy -94.10 kcal/mol through 5 hydrogen bonds. It showed the best ADME and toxicity profiling and higher affinity values than other potent candidate and market drugs such as atorvastatin and rosuvastatin. Therefore, it is suggested for further in vivo investigation, the druggability of 5j and its cholesterol regulatory impact on AD.

Differentials in Cardiovascular Risk Factors and Diabetes by Socioeconomic Status and Sex in Kalutara, Sri Lanka.

Since 1950, cardiovascular disease (CVD) has emerged as a leading cause of mortality in Sri Lanka, especially in men. In 2014, a survey in Kalutara to assess CVD and type 2 diabetes mellitus (T2DM) risk factors in adults aged 25 to 64 years (n = 1011), and associations with sex and socioeconomic status (SES), found similar CVD risk factors in both sexes, except for daily tobacco smoking at 19% in men and nil in women, and higher body mass index (BMI) in women than men. With increasing SES in men, there were significant linear increases in mean BMI, waist circumference, mean systolic and diastolic blood pressure, mean fasting plasma glucose, and T2DM prevalence, but decreases in tobacco smoking. Whereas in women higher SES was associated with a significant increase in mean BMI, but a significant decrease in hypertension prevalence. Tobacco smoking is the main risk factor explaining higher CVD mortality in men compared with women.