Atherosclerotic cardiovascular disease (ASCVD) is currently the most common cause of death in the United States. Some dietary factors contribute importantly to ASCVD and other factors can reduce risk of ASCVD. Oleic acid is a monounsaturated fatty acid (MUFA). Dietary patterns in which oleic acid contributes to a majority of dietary fatty acids are associated with reduced ASCVD risk. These beneficial effects are due to MUFA-induced lipoprotein profile changes such as decreases in low density lipoprotein (LDL) and increases in high density lipoprotein (HDL). LDL oxidation plays a central role in atherosclerosis development as it both initiates and propagates atherosclerosis. HDL is anti-atherogenic as it can attenuate LDL oxidation. HDLs are a class of diverse lipoprotein that varies in protein and enzymatic composition. The paraoxonase (PON) family of enzymes, especially PON1, is primarily expressed in the liver; PON activity in the circulatory system is associated with HDL. Both PON and HDL have been documented to be anti-atherogenic. Other factors such as homocysteine and C-reactive protein (CRP) can also be considered risk factors for ASCVD. However, studies of risk factors in healthy men who consume ground beef with a different content of MUFA are lacking; hence, no conclusive evidence has established whether consuming a high amount of MUFA in the form of ground beef alters the development of atherosclerosis. The overall purpose of this study was to investigate whether the provision of ground beef with a fractionally higher MUFA content could lower or improve several ASCVD risk factors in men who consume ground beef. These risk factors include the metabolic indices of glucose, insulin and homeostasis model assessment (HOMA), inflammation risk factors of CRP and homocysteine and anti-risk factor of paraoxonase. The concentration of homocysteine was determined spectrophotometrically following separation by high pressure liquid chromatography (HPLC). Enzyme-linked imminosorbent assay kits that measured the CRP and insulin concentration in plasma. The significance of the results was determined by subjecting the data to ANOVA using the general linear model for repeated measurement (P<0.05). From this study, it can be concluded that MUFA has a beneficial effect of lowering risks as determined by metabolic indices and lipoprotein profile. Moreover, our study showed that different concentrations of MUFA in ground beef has no effect on PON1 activity, but that increased beef consumption generally reduces PON1 in association with increases in homocysteine concentration while improving indicators of glucose tolerance.

The relationship between cardiovascular conditions and the presence of Alzheimer's disease (AD) has been well-documented in a number of recent studies. Generally, the presence of cardiovascular conditions such as high total cholesterol and hypertension have been shown to significantly increase the risk for the development of AD. Given the results of these studies, it is possible that these same risk factors might also increase the risk of developing mild cognitive impairment (MCI). An analysis of 216 subjects (119 cognitively normal (CN), 77 aMCI, 20 naMCI) found that after adjusting for age, education, ethnicity, and gender, only hemoglobin A1c (HbA1c) showed a significant effect for aMCI [OR = 1.75 (1.02, 2.99) p=0.04]. Age and education also showed significant effects that were consistent with previous studies. Given recent studies linking Type 2 diabetes with AD, this finding appears to strengthen the link between diabetes-related disease processes and aMCI/AD disease processes.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Hyperhomocysteinemia, a condition of elevated blood homocysteine level, is an independent risk factor for cardiovascular diseases. Folic acid can effectively reduce blood homocysteine levels. Recent studies have shown that hyperhomocysteinemia is also associated with liver disorders. However, the underlying mechanisms remain unclear. The general objective of my study was to investigate the biochemical and molecular mechanisms of homocysteine-induced liver injury and abnormal lipid metabolism. Hyperhomocysteinemia was induced in Sprague-Dawley rats by feeding a high-methionine diet for 4 weeks. An elevation of serum aminotransferases activities (indicator for liver injury) and an increase in hepatic lipid peroxidation were observed in hyperhomocysteinemic rats. Hyperhomocysteinemia-induced superoxide anion production led to oxidative stress in the liver. Reduction of oxidative stress by inhibiting superoxide anion production ameliorated hyperhomocysteinemia-induced liver injury. A significant elevation of hepatic and serum cholesterol concentrations in hyperhomocysteinemic rats was observed, exclusively due to increased expression of HMG-CoA reductase in hepatocytes. The molecular mechanisms of homocysteine-induced adverse effects were further investigated in isolated rat hepatocytes and in human hepatoma cells (HepG2). Hcy stimulated HMG-CoA reductase expression in hepatocytes via activation of transcription factors, namely, sterol regulatory element-binding protein-2 (SREBP-2), cAMP response element binding protein (CREB) and nuclear factor Y (NF-Y). Activation of these 3 transcription factors was detected in hyperhomocysteinemic rat liver and in homocysteine-treated hepatocytes. Pretreatment of hepatocytes with inhibitors for individual transcription factors effectively attenuated Hcy-induced HMG-CoA reductase mRNA expression. Supplementation of folic acid in diet significantly reduced serum homocysteine level and effectively inhibited hyperhomocysteinemia-induced superoxide anion production, resulting in amelioration of oxidative stress-mediated liver injury in hyperhomocysteinemic rats. These results reflected a protective role of folic acid in hyperhomocysteinemia-induced liver injury. In conclusion, the present study demonstrates that (1) hyperhomocysteinemia can cause oxidative stress and liver injury; (2) homocysteine stimulates cholesterol biosynthesis in hepatocytes via transcriptional regulation of HMG-CoA reductase expression; (3) supplementation of folic acid offers a hepatoprotective effect during hyperhomocysteinemia. Oxidative stress and accumulation of cholesterol in the liver contribute to liver injury associated with hyperhomocysteinemia. The role of folic acid in maintaining good health may extend beyond the cardiovascular system to encompass hyperhomocysteinemia-associated liver disorders.

Hyperhomocysteinemia, a condition of elevated blood homocysteine level, is an independent risk factor for cardiovascular diseases. Folic acid can effectively reduce blood homocysteine levels. Recent studies have shown that hyperhomocysteinemia is also associated with liver disorders. However, the underlying mechanisms remain unclear. The general objective of my study was to investigate the biochemical and molecular mechanisms of homocysteine-induced liver injury and abnormal lipid metabolism. Hyperhomocysteinemia was induced in Sprague-Dawley rats by feeding a high-methionine diet for 4 weeks. An elevation of serum aminotransferases activities (indicator for liver injury) and an increase in hepatic lipid peroxidation were observed in hyperhomocysteinemic rats. Hyperhomocysteinemia-induced superoxide anion production led to oxidative stress in the liver. Reduction of oxidative stress by inhibiting superoxide anion production ameliorated hyperhomocysteinemia-induced liver injury. A significant elevation of hepatic and serum cholesterol concentrations in hyperhomocysteinemic rats was observed, exclusively due to increased expression of HMG-CoA reductase in hepatocytes. The molecular mechanisms of homocysteine-induced adverse effects were further investigated in isolated rat hepatocytes and in human hepatoma cells (HepG2). Hcy stimulated HMG-CoA reductase expression in hepatocytes via activation of transcription factors, namely, sterol regulatory element-binding protein-2 (SREBP-2), cAMP response element binding protein (CREB) and nuclear factor Y (NF-Y). Activation of these 3 transcription factors was detected in hyperhomocysteinemic rat liver and in homocysteine-treated hepatocytes. Pretreatment of hepatocytes with inhibitors for individual transcription factors effectively attenuated Hcy-induced HMG-CoA reductase mRNA expression. Supplementation of folic acid in diet significantly reduced serum homocysteine level and effectively inhibited hyperhomocysteinemia-induced superoxide anion production, resulting in amelioration of oxidative stress-mediated liver injury in hyperhomocysteinemic rats. These results reflected a protective role of folic acid in hyperhomocysteinemia-induced liver injury. In conclusion, the present study demonstrates that (1) hyperhomocysteinemia can cause oxidative stress and liver injury; (2) homocysteine stimulates cholesterol biosynthesis in hepatocytes via transcriptional regulation of HMG-CoA reductase expression; (3) supplementation of folic acid offers a hepatoprotective effect during hyperhomocysteinemia. Oxidative stress and accumulation of cholesterol in the liver contribute to liver injury associated with hyperhomocysteinemia. The role of folic acid in maintaining good health may extend beyond the cardiovascular system to encompass hyperhomocysteinemia-associated liver disorders.

Homocysteine, an independent risk factor for cardiovascular disease, is methylated in the liver via the zinc metalloenzyme betaine-homocysteine methyltransferase (BHMT). Established assays for BHMT include a radiochemical assay, a colorometric assay, an HPLC assay and an in vivo microbiological assay. These techniques are either unsuitable for substrate specificity studies, or are unable to give kinetic measurements. BHMT was purified from liver and measured directly and kinetically by a novel ¹H-NMR spectroscopic assay. The disappearance of substrates and the formation of products are monitored simultaneously. Using 2 mM glycine betaine and homocysteine as substrates in 20 mM phosphate buffer (pH = 7.5) and measuring the production of N,N-dimethylglycine the CV is 6.3% (n = 6) and the detection limit is 6 nkatal. An endpoint assay for BHMT activity was also developed and had CV = 5.3%, n = 6, with a detection limit of 2 nkatal. The NMR spectroscopic assay was used to determine the substrate specificity with a library of alternative substrates. Analysis of betaine analogues with different chain length, α-substitution, substitution of the nitrogen and carboxyl moieties demonstrated that BHMT is inactive if there is any steric crowding of the nitrogen or α-carbon positions. BHMT is capable of using group VI heteroatom betaines as methyl donors, with much faster rates than glycine betaine. For glycine betaine the Km was 0.19 ± 0.03 mM with a Vmax of 17 ± 0.7 nMol min-1 mg-1. The same assay was used to detect and partially characterise a BHMT activity from hagfish liver that is similar to that of the mammalian enzyme. NMR spectroscopy was adapted for measurements of glycine betaine in urine, along with other medically significant methylamines. These were shown to be valid for clinical use and in animal studies. A novel metabolite of the sulfonium analogue of glycine betaine (methylsulfinylmethanoate) was identified in rats.

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Kardiyoloji Anabilim Dalı, 2006. / Bibliyografya var.

Thesis (Ph. D.)--Oregon State University, 2008. / Printout. Includes bibliographical references. Also available on the World Wide Web.

Resumo: Estudos recentes indicam que um nível plasmático elevado de homocisteína é um fator de risco importante e prevalente para doença vascular aterosclerótica coronariana, cerebral e periférica, e para as doenças tromboembólicas. A homocisteína é um aminoácido sulfurado sintetizado em condições fisiológicas a partir da metionina alimentar, sendo utilizado em diversas vias metabólicas. A hiperhomocisteinemia, definida como nível plasmático acima de 15 μmol/L, pode ser atribuída a ocorrência de defeitos genéticos de algumas enzimas do metabolismo da homocisteína, ou à deficiências nutricionais das vitaminas B6, B12 e folato, ou ainda, estar relacionada à outros fatores de risco para aterosclerose, como a obesidade, a dislipidemia, a hipertensão arterial e o hábito tabágico. Foram sugeridos alguns mecanismos biologicamente plausíveis de dano vascular causado pelo aumento da homocisteína no plasma, incluindo agressão direta ao endotélio, indução do estresse oxidativo na parede vascular, alteração na produção de óxido nítrico, alterações das propriedades antitrombóticas e oxidação de lipoproteínas. Com o objetivo de avaliar a freqüência de hiperhomocisteinemia e a sua relação com indicadores relacionados ao estado nutricional (antropométrico, dietético e laboratorial), foi realizado um estudo transversal (cross-sectional ) com 40 pacientes (mediana 61 anos) portadores de doença arterial periférica atendidos no Hospital das Clínicas da Faculdade de Medicina de Botucatu (UNESP). Detectou-se freqüência elevada de pacientes portadores de isquemia crônica de membros (75%), com diagnóstico de sobrepeso (32,5%) ou obesidade (20%), com aumento da adiposidade corporal (100%) e redução da massa muscular (62,5 a 71%), com ingestão insuficiente das vitaminas B6 (85%), B12 (60%) e folato (72,5%)... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Recent studies denotes a high plasmatic level of homocysteine is a important factor of risk and prevalent to cardiovascular, cerebral and peripheral atherosclerotic diseases, and to thromboembolic diseases. Homocysteine is a synthesized sulfur amino acid in physiologic conditions derived to alimentary methionine, it has been used in various metabolism ways. Hyperhomocysteinemia, defined as a plasmatic level above 15μ mol/ L, can be attributed to the occurrence of genetics defect of some enzymes from the metabolism of homocysteine, or of the nutritional deficiency of vitamins B6, B12 and folate, or further, be related to the others factors of risk to atherosclerosis such as obesity, dyslipidemia, hypertension and smoking. It was suggested that some plausible biological mechanisms of vascular damage caused by the increase of homocysteine in the plasma, including oxidative stress in the vascular wall, modification in the production of nitric oxide, modification of the antithrombotics proprieties and oxidation of lipoproteins. The main goal to evaluate the frequency of hyperhomocysteinemia and its relation to the indicators related to the nutritional condition (anthropometric, dietetics and laboratorial), it was accomplished a cross-sectional study among 40 patients (median 61 years) with peripheral arterial disease attended at the Hospital of Medicine School in Botucatu (UNESP). It was detected a high frequency of patients with chronic limb ischemia (75%), overweight diagnosis (32,5%) or obesity (20%), increase of corporal adiposity (100%) and reduce of muscular mass (62,5% to 71%), insufficient intake of vitamins B6 (85%), B12 (60%) and folate (72,5%) and exceeding of protein (80%) and methionine (85%), increased serum level of triglyceride (52,5%), total cholesterol (60%), LDL- c (95%) and reduce of HDL-c (60%). Hyperhomocysteinemia was found in 60% of the patients... (Complete abstract, click electronic access below) / Orientador: Winston Bonetti Yoshida / Coorientador: Roberto Carlos Burini / Mestre

A olanzapina é um fármaco antipsicótico atípico utilizado no tratamento da esquizofrenia. Como efeitos adversos relacionados ao seu uso encontram-se obesidade, hiperlipidemia, diabetes mellitus tipo 2 e hipertensão, podendo acarretar no desenvolvimento de síndrome metabólica. O presente trabalho tem por objetivo realizar a monitorização terapêutica em pacientes na terapia com olanzapina, estabelecendo uma possível correlação entre a dose-concentração plasmática e a potenciação do risco a reações adversas, constituindo suporte clínico na eficácia do tratamento. A análise dos parâmetros antropométricos (peso, índice de massa corpóreo, circunferência do braço, circunferência do abdome, circunferência do quadril, prega cutânea triciptal, prega cutânea biciptal, prega cutânea subescapular, prega cutânea suprailíaca, resistência, porcentagem de massa gorda e taxa metabólica basal), parâmetros hemodinâmicos (pressão arterial sistólica, pressão arterial diastólica e freqüência cardíaca) e parâmetros bioquímicos (aspartato aminotranferase, alanina aminotransferase, gama glutamiltransferase, creatinina, ácido úrico, amilase, insulina, bilirrubinas, glicemia, cálcio, sódio e potássio), perfil lipídico (colesterol total, LDLcolesterol, HDL-colesterol e triglicérides), concentração de homocisteína e proteína C reativa, são relevantes na medida em que representam marcadores importantes de alterações relacionadas a desordens metabólicas ou de risco aterosclerótico. Como a obesidade e as coronariopatias podem induzir tais alterações, é importante avaliar qual o risco que o aumento de peso induzido pela olanzapina traz para o paciente esquizofrênico. A análise estatística foi realizada utilizando-se um modelo linear de efeito misto, apropriado para análise de medidas realizadas ao longo de um período pré-estabelecido. O nível de significância foi fixado em p<0,05. / The olanzapine is an atypical antipsychotic drug used to treat schizophrenia. How adverse effects related to its use, are obesity, hyperlipidemia, diabetes mellitus type II and hypertension, may result in the development of metabolic syndrome. This study aims to carry out monitoring therapy in patients in treatment with olanzapine, establishing a possible correlation between the dose-plasma concentration and potentiation of the risk to adverse reactions, providing clinical support in the effectiveness of treatment. Analysis of anthropometric parameters (weight, body mass index, arm circumference, circumference of the abdomen, the hip circumference, triceps skinfold thickness, biciptal skin fold, subscapular skin fold, skin fold suprailíaca, strength, percentage of fat mass and metabolic rate basal), hemodynamic parameters (systolic blood pressure, diastolic blood pressure and heart rate) and biochemical parameters (aspartate aminotranferase, alanine aminotransferase, gamma glutamyl transferase, creatinine, uric acid, amylase, insulin, total bilirubin, glucose, calcium, sodium and potassium ), lipid profile (total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides), concentration of homocysteine and C-reactive protein, are relevant in so far represent important markers of changes related to metabolic disorders and atherosclerotic risk. As obesity and coronary diseases can induce such changes, which is important to evaluate the risk that the weight gain induced by olanzapine brings to the schizophrenic patient. Statistical analysis was performed using a mixed effect linear model, suitable for analysis of measurements taken over a pre-established. The significance level was set at p <0.05.