To see the other types of publications on this topic, follow the link: LDL.
Dissertations / Theses on the topic 'LDL'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'LDL.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Liu, Ming-Lin. "LDL oxidation and LDL particle size in the development of atherosclerosis." Helsinki : University of Helsinki, 2002. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/liu/.
Full text
2
Matyas, Angela. "The Functional Characterization of PCSK9's Binding Interactions with LDL and the LDL Receptor." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/40592.
Full textAbstract:
Elevated plasma cholesterol is a risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) hinders the uptake of low-density lipoprotein cholesterol (LDL-c) by mediating degradation of LDL receptors (LDLRs) in the liver. Gain-of-function (GOF) mutations in PCSK9 cause familial hypercholesterolemia (FH). In normolipidemic human plasma, 30-40% of PCSK9 is bound to LDL particles, and this association with LDL inhibits PCSK9’s ability to mediate LDLR degradation in cultured cells. To further investigate the physiological relevance of this interaction, we analyzed natural GOF mutations in PCSK9 and assessed their effects in vitro on LDL binding, LDLR binding and LDLR degradation. Our results indicate that several GOF mutations severely inhibit LDL binding compared to wild type (WT) PCSK9, and only modestly affect LDLR affinity and LDLR degradation. These findings shed light on the potential physiological relevance of the PCSK9-LDL interaction, which may have an inhibitory effect on PCSK9 activity in vivo.
3
Meilhac, Olivier. "Ldl oxydees et atherosclerose. Mecanismes d'oxydation des ldl, effets de bcl-2 et des antioxydants sur la cytotoxicite des ldl oxydees." Toulouse 3, 1998. http://www.theses.fr/1998TOU30124.
Full textAbstract:
Les lipoproteines de basse densite oxydees (ldlox) sont fortement impliquees dans l'atherosclerose (une des premieres causes de mortalite dans les pays industrialises). Elles participent a la formation de stries graisseuses, et a l'evolution des lesions vers des stades irreversibles de la maladie. Les ldl, en s'oxydant au cours de leur passage dans l'espace sous-endothelial, presentent de nombreuses proprietes et deviennent notamment cytotoxiques envers differents types cellulaires de la paroi vasculaire. Dans ce travail, nous nous sommes interesses aux mecanismes d'oxydation des ldl et de cytotoxicite des ldlox. Nous rapportons que les mitochondries et la production d'ion superoxyde sont impliquees dans l'oxydation des ldl par les cellules endotheliales humaines (ceh) en culture. L'utilisation d'inhibiteurs de la chaine respiratoire mitochondriale, d'agents decouplants, et la destruction selective des mitochondries par photosensibilisation (sans alteration de la viabilite cellulaire) induisent une diminution de production d'ion superoxyde et inhibent l'oxydation des ldl (arterioscler. Thromb. Vasc. Biol. , 1997, 17 : 1575-1582). Dans la deuxieme partie de notre travail, nous avons mis en evidence une cytotoxicite des ldlox se traduisant par une apoptose massive des ceh, impliquant des voies dependantes de calcium, et inhibee par des acides phenoliques d'origine alimentaire (arterioscler. Thromb. Vasc. Biol. , 1997, 17 : 331-339 et br. J. Pharmacol. , 1998, 123 : 565-573). De plus, les ldlox induisent une augmentation des hydroperoxydes intracellulaires, pouvant participer a la toxicite des ldlox et qui peut etre bloquee par des antioxydants. Enfin, une forte expression de bcl-2 (proteine anti-apoptotique) protege de l'apoptose mais pas de la cytotoxicite des ldlox envers des cellules promyelocytaires et des lymphocytes sanguins humains, suggerant un role proinflammatoire (via la necrose) de cette proteine dans l'atherosclerose.
4
Yuahasi, Katia Kioko. "Mecanismos de formação da LDL eletronegativa (LDL-): efeito da glicoxidação e da lipólise." Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-09122016-143030/.
Full textAbstract:
A fração plasmática da lipoproteína de baixa densidade (LDL) é formada por partículas de diferentes tamanhos, carga e densidade. Baseada na diferença de carga das partículas, a LDL pode ser subfracionada em LDL nativa (nLDL) e LDL eletronegativa (LDL‾). A LDL‾ está presente no plasma e possui propriedades aterogênicas e pró-inflamatórias, assim como, possui menor concentração de antioxidantes lipossolúveis, maior concentração de dienos conjugados, alterações conformacionais da apoliproteína B-100 e menor afinidade para o receptor da LDL em comparação com a nLDL. Concentrações elevadas de LDL‾ têm sido observadas em pacientes com alto risco para o desenvolvimento de doenças cardiovasculares, incluindo hipercolesterolemia familiar, diabetes. Considerando-se que os mecanismos envolvidos na formação endógena da LDL‾ ainda não estão elucidados, neste estudo foi investigado o efeito da glicoxidação e da lipólise sobre a partícula LDL para avaliar a contribuição destes processos para a formação da LDL‾ in vitro e in vivo. As modificações químicas da LDL e da imunorreatividade com anticorpo monoclonal anti-LDL‾ foi analisada antes e depois da incubação do plasma com lipoproteína lipase (LPL) ou fosfolipase A2 (PLA2), assim como mimetizando-se a lipólise intravascular. Além disso, na lipólise in vivo foi monitorado no periodo pós-prandial em indivíduos normolipidêmicos para investigar a LDL‾ formada endogenamente. A contribuição da glicoxidação para a geração de LDL‾ foi avaliada in vitro pela incubação da LDL com glicose. O efeito da glicoxidação endógena foi monitorada pela medida, ex-vivo, dos os produtos de glicação avançada (AGEs) e LDL‾ no plasma de pacientes diabéticos tipo I (DM I), tipo II (DM II) e indivíduos intolerantes à glicose (IGT). O processo de glicação não enzimática, in vitro, resultou no aumento da concentração de LDL‾. Os indivíduos dos grupos DM I, DM II e IGT apresentaram concentrações plasmáticas elevadas de LDL‾ em relação aos seus respectivos controles, enquanto observou-se aumento de AGEs apenas nos grupos DM I e DM II. O processo de lipólise in vitro mediado pela LPL e PLA2, induziu aumento significante da concentração de LDL‾; entretanto, somente pela ação da LPL foi associada com modificações oxidativas. Em concordância, o processo de lipólise in vivo (pós-prandial) também promoveu aumento significativo da concentração de LDL‾ associado com modificações oxidativas. Conclusão, nossos dados mostram que, glicoxidação e de lipólise, poderiam contribuir na formação da LDL‾ in vivo.The low density lipoprotein (LDL) fraction in blood plasma is formed by particles with different size, charge and density. Based on particle charge differences, LDL fraction may be separated into native (nLDL) and electronegative (LDL‾) subfractions. LDL‾ is present in blood plasma and has atherogenic and proinflammatory properties, as well as, lower concentrations of lipid soluble antioxidants, higher content of conjugated dienes, conformational alterations of apolipoprotein B-100 and lower affinity by LDL receptor in comparison to nLDL. Increased LDL‾ concentrations have been found in subjects with high risk for cardiovascular diseases, including those with familiar hypercholesterolemia, diabetes and hyperlipidemia. Considering that the mechanisms involved in the endogenous generation of LDL‾ are not yet well elucidated, in this study the effect of glucoxidation and lipolysis of LDL particles was investigated in order to evaluate their contribution to in vitro e in vivo LDL‾ formation. LDL chemical modifications and its reactivity towards a monoclonal anti-LDL‾ antibody were analyzed before and after incubation of either plasma or LDL with lipoprotein lipase (LPL) or phospholipase A2 (PLA2) as an in vitro lipolysis biomimetic system. Moreover, in vivo lipolysis was monitored at the post-prandial period in normolipidemic subjects to investigate LDL‾ endogenously formed. The contribution of glucoxidation to LDL‾ generation was evaluated in vitro by incubating LDL with glucose. The effect of endogenous glucoxidation was monitored by ex-vivo measurement of advanced glycation end products (AGES) and LDL‾ in blood plasma of type I (DM I) and II (DM II) diabetic patients, as well as, in subjects with glucose intolerance (IGT). The in vitro non-enzymatic glycation resulted in increased LDL‾ formation. The DM I, DM II and IGT groups showed higher LDL‾ concentrations than the respective control groups, while AGEs were increased only in DM I e DM II groups. The in vitro lipolysis mediated by LPL and PLA2 induced a significant increase of LDL‾; however, only LPL action was also associated to LDL oxidative modification. In accordance, in vivo lipolysis (post-prandial) also promoted a significant increase of LDL‾ levels associated to LDL oxidative modification. In conclusion, our data show that both, glycoxidation and lipolysis, could contribute to in vivo LDL‾generation.
5
Teixeira, Luciane dos Santos. "Estudos das propriedades ópticas dos complexos európio tetraciclinas e suas aplicações na detecção de lipoproteínas." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/85/85134/tde-12082011-133857/.
Full textAbstract:
Este trabalho apresenta as propriedades ópticas dos complexos Európio Tetraciclinas (EuTcs) na presença de LDL e de LDL oxidada com potenciais aplicações em análises clínicas. Foram escolhidos quatro elementos da família das Tetraciclinas: Tetraciclina (Tc), Clorotetraciclina (CTc), Metatetraciclina (MTc) e Oxitetraciclina (OTc) para fazerem parte dos complexos com o íon európio. As melhores condições para se formar os complexos eficientemente foram determinadas, através das medidas dos parâmetros ópticos como: absorção, emissão e de tempo de vida. As melhores concentrações de európio nos complexos EuTcs e possíveis influências de íons inorgânicos normalmente presentes no plasma sanguíneo também foram analisadas. As amostras foram preparadas em pH neutro e a luminescência visível do lantanídeo foi detectada após tempo de repouso das amostras de 15 minutos. Os resultados deste trabalho mostraram que as moléculas de LDL e de LDL oxidada apresentaram um importante papel no aumento da intensidade de emissão dos complexos das Tcs. As medidas realizadas com os complexos EuTcs não apresentaram deslocamentos nos comprimentos de onda dos espectros de absorção e de emissão na presença de LDL, o que demonstra a ausência de interação direta entre as moléculas de Tcs e as moléculas de LDL e LDL oxidada. No entanto, o íon európio pode interagir em diferentes sítios das moléculas de tetraciclinas o que diferenciou a intensidade de emissão de cada complexo. Comparando os resultados obtidos entre os complexos de EuTcs, o complexo EuTc foi o que apresentou perspectivas promissoras na quantificação de LDL e LDL oxidada.This work presents the optical properties of europium complexes - Tetracyclines (EuTcs) in the presence of LDL and oxidized LDL with potential applications in clinical analysis. Four elements were chosen from the Tetracyclines family: Tetracycline (Tc), Chlortetracycline (CTc), Metatetraciclina (MTc) and Oxytetracycline (OTc) to be part of complexes with europium ion. The best conditions to form the complex efficiently were determined through measurements of optical parameters such as absorption, emission and lifetime. The best concentrations of europium complexes in EuTcs and possible influences of inorganic ions normally present in blood plasma were also analyzed. The samples were prepared at neutral pH and the visible luminescence of lanthanide was detected after resting time of the samples of 15 minutes. These results showed that the molecules of LDL and oxidized LDL have an important role in increase of the emission intensity for Tcs complexes . The measurements performed with the complex EuTcs showed no shifts in the wavelengths of the absorption and emission spectra in the presence of LDL, which demonstrates the absence of direct interaction between the molecules of Tcs and the molecules of LDL and oxidized LDL. However, the europium ion can interact at different sites of the tetracyclines molecules which differed the emission intensity of each complex. Comparing the results obtained between the complexes EuTcs, the complex EuTc is the one that presented the promising prospects in the quantification of LDL and oxidized LDL.
6
Höppner, Jens. "Der LDL-Rezeptor und das LDL-Rezeptor-related-Protein als Recyclingrezeptoren für triglyceridreiche Lipoproteine." [S.l.] : [s.n.], 2000. http://www.sub.uni-hamburg.de/disse/169/Disse.pdf.
Full text
7
O'Hagan, C. E. "Physiological catalysts of LDL oxidation." Thesis, Queen's University Belfast, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.396887.
Full text
8
Cohen, Danielle. "Lipoproteína de baixa densidade oxidada (LDLox) versus lipoproteína de baixa densidade eletronegativa [LDL(-)] de adolescentes: análise comparativa." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/89/89131/tde-19032014-165411/.
Full textAbstract:
A obesidade é considerada uma doença crônica e multifatorial, onde eventos como a inflamação de baixa intensidade e as modificações oxidativas estão presentes. A elevada prevalência de obesidade tem impacto direto no desenvolvimento precoce de diabetes mellitus, hipertensão e outros fatores de risco cardiovasculares. Esse perfil tem motivado a identificação de biomarcadores precoces, sendo o monitoramento da lipoproteína de baixa densidade oxidada (LDLox) e lipoproteína de baixa densidade eletronegativa [LDL(-)] potenciais candidatos. Diante do exposto, o objetivo deste estudo foi realizar a análise comparativa e de correlação entre o conteúdo de LDLox e [LDL(-)] em adolescentes. Foram selecionados 137 adolescentes de ambos sexos, com faixa etária de 10 a 19 anos e regularmente em matriculados em escolas públicas da cidade de São Paulo. O peso, altura e circunferência da cintura (CC) foram avaliados. Após jejum (12h-15h) foi coletada uma amostra de sangue e, a partir do plasma, foram realizadas as seguintes análises: glicose, insulina, perfil lipídico, apolipoproteína (AI e B), ácidos graxos não esterificados, tamanho de HDL, atividade da CETP e LDL(-) e LDLox. Os resultados encontrados foram analisados por meio do programa SPSS 15.0, considerando valor de significância de p< 0,05. Os 137 adolescentes foram distribuídos em dois grupos: 71 no Eutrófico (51,82%) e 66 no Obeso (48,18%), segundo a classificação do IMC. 48 (35,04%) dos adolescentes eram do sexo masculino e 89 (64,96%) do sexo feminino, com idade média de 14,2 (2,3) anos. Em relação à CC, observou-se que essa confirmou a classificação feita pelo IMC. Observou-se também uma maior prevalência de hipertensão (65% p = 0,011) e obesidade (64,7% p=0,041) nos antecedentes familiares do grupo Obeso quando comparado ao grupo Eutrófico. Os adolescentes obesos apresentaram maiores valores de triglicerídeos, HDL, APO B, CETP, insulina e LDL(-) e LDLox, quando comparados aos eutróficos. Perfil inverso foi observado para Apo AI. O conteúdo de LDLox e LD(-) variou significativamente em função do IMC. Entretanto, essas partículas de LDLs não se correlacionaram entre si, embora tenham apresentado associação com outros parâmetros cardiometabólicos. Os resultados obtidos confirmam o impacto negativo da obesidade sobre os parâmetros cardiometabólicos de adolescentes e, apesar do conteúdo de LDLox e LDL(-) ter aumentado em função do IMC, essas partículas parecem ser estruturalmente distintas. Essa possibilidade foi reforçada pelas diferentes associações dessas partículas com outros marcadores bioquímicos.Obesity is considered a chronic and multifactorial disease, where events such as low intensity inflammation and oxidative modifications are present. The high prevalence of obesity has a direct impact on the early development of diabetes mellitus, hypertension and other cardiovascular risk factors. This profile has motivated the identification of early biomarkers, and monitoring the oxidized low density lipoprotein (oxLDL) and electronegative low-density lipoprotein [LDL (-)] are potential markers. The aim of this study was to conduct a comparative analysis and correlation between the content of oxLDL and [LDL (-)] in adolescents. We selected 137 adolescents of both sexes, aged 10-19 years, enrolled in public schools in the city of São Paulo. The weight, height, waist circumference (WC) were assessed. After fasting (12-15h) samples of blood were collected and from plasma were performed the following analyzes: glucose, insulin, lipid profile, apolipoprotein (AI and B), NEFA, HDL size, CETP activity and LDL (-) and oxLDL. The results were analyzed by using SPSS 15.0 considering significant value of p <0.05. The 137 adolescents were divided into two groups: 71 Normal Weight (51.82%) and 66 Obese (48.18%), according to BMI classification. 48 (35.04%) of the adolescents were male and 89 (64.96%) females with a mean age of 14.2 (2.3) years. Regarding the CC observed, it confirmed the classification made by BMI. There was a higher prevalence of hypertension (65% p = 0.011) and obesity (64.7% p = 0.041) in the family history group Obese when compared to normal weight. Obese adolescents had higher triglyceride, HDL, APO B, CETP, insulin and LDL (-) and oxLDL, compared to normal weight. Reverse profile was observed for Apo AI. The content of oxLDL and LDL (-) varied significantly according to BMI. However, these LDL particles were not correlated with each other, although they showed cardiometabolic combination with other parameters. The results confirm the negative impact of obesity on cardiometabolic parameters of teenagers and although the content of oxLDL and LDL (-) increased as a function of BMI, these particles appear to be structurally distinct. This possibility was reinforced by different associations of these particles with other biochemical markers.
9
Sarkar, Samantha Khadija. "Asociation of PCSK9 with Low Density Lipoproteins (LDL) in the Regulation of LDL-Cholesterol Levels." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/32825.
Full textAbstract:
Proprotein Convertase Subtilisin / Kexin Type-9 (PCSK9) has emerged as a major regulator of plasma cholesterol levels. PCSK9 is secreted mainly from the liver and circulates as a plasma protein. PCSK9 binds cell surface low-density lipoprotein (LDL) receptors and mediates their degradation upon endocytosis in the liver. This decreases the liver’s ability to clear LDL-cholesterol from the blood. PCSK9 is also capable of binding LDL particles themselves; this interaction inhibits the ability of PCSK9 to bind and mediate LDLR degradation in cultured hepatic cells, but its effect on PCSK9 function in vivo remains unknown. A disordered N-terminal region of the PCSK9 prodomain is necessary for binding to isolated LDL particles in vitro. This N-terminal region is also autoinhibitory to PCSK9-LDL receptor binding. We hypothesized that the N-terminal of the PCSK9 prodomain plays a role in an allosteric mechanism that regulates PCSK9 function. Through mutagenesis studies, we found that both a conserved stretch of acidic residues and an adjacent conserved stretch of hydrophobic residues are crucial for the PCSK9-LDL interaction; the hydrophobicity of the residue at position 38 (Tyr) within the conserved acidic stretch was also found to be important for this. Helical wheel modeling of the prodomain N-terminal sequence revealed the potential for a lipid-ordered amphipathic helix to form, which may aid PCSK9 docking onto LDL. Replacing residues A44 and L41 with helix-disrupting proline residues abolished LDL binding. Co-pelleting ultracentrifugation assays also show that wild-type PCSK9 is capable of associating with liposomes, while the A44P mutation disrupts this lipid association. The A44P-PCSK9 mutation, showing an 80-90% decrease in LDL association but with LDL receptor binding and degrading functions intact, may serve as an important tool in future studies investigating the PCSK9-LDL interaction in vivo. Elucidation of the mechanism by which LDL-binding naturally inhibits PCSK9 activity may also help to develop new anti-PCSK9 therapeutics in the future.
10
Hoshikawa, Hajime. "High affinity binding of oxidized LDL to mouse lectin-like oxidized LDL receptor (LOX-1)." Kyoto University, 1999. http://hdl.handle.net/2433/182282.
Full text
11
Knothe, Ingrid. "Analyse der Low-Density-Lipoproteine (LDL) kann die LFE die UZ-Fraktionierung von LDL ersetzen? /." [S.l. : s.n.], 2005.
Find full text
12
Fernandez, Diana Gabriela Estevez. "Influência do ω-3 sobre a lipoproteína de baixa densidade eletronegativa [LDL(-)], anticorpos LDL(-) e tamanho das partículas de LDL em indivíduos com síndrome metabólica." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/89/89131/tde-04052015-115858/.
Full textAbstract:
Introdução A Síndrome Metabólica (SM) representa um conjunto de fatores que determinam maior risco para Doença Cardiovascular (DCV), devido principalmente à Resistência à Insulina (RI) e ao estado inflamatório promovido pelo tecido adiposo branco hipertrofiado. Nesse contexto, a condição de dislipidemia favorece o desenvolvimento da aterosclerose, devido a que maiores concentrações de lipoproteína de baixa densidade (LDL) no plasma podem propiciar modificações nessas partículas. Essas modificações podem ter origem oxidativa ou não oxidativa e impactar nas características aterogênicas da LDL. O ômega três tem mostrado efeitos hipolipemiantes e anti-inflamatórios, que podem reduzir o risco cardiovascular de indivíduos com SM. Objetivo:: avaliar o efeito da suplementação de 3g de ω-3 por um período de oito semanas sobre a concentração plasmática das partículas de LDL eletronegativas [LDL(-)] e seus anticorpos, assim como monitorar possíveis mudanças nas concentrações das subfrações das LDL. Metodologia: Foram incluídos 115 participantes de ambos os sexos, entre 30 e 74 anos, com SM, separados nos grupos de intervenção com ω-3 (n=58) e controle com ω-9 (n=57). Foram realizadas análises de perfil lipídico e por meio de ELISA foram avaliadas a concentração de LDL(-) e de antiLDL(-) no plasma dos participantes. O tamanho das subfrações de LDL foi realizado no sistema Lipoprint. O efeito do tempo e das intervenções foi testado por meio do programa SPSS versão 20.0, adotando-se o concentração de significância de p<0,05. Resultados: A suplementação de ω-3 teve efeito significativo na redução do % de massa grassa (%MG) e na pressão arterial sistólica (4%) e diastólica (5%). Em relação ao perfil lipídico, ambas intervenções tiveram efeitos significativos de redução de colesterol total (CT), LDL-c, não HDL (nHDL) e triacilglicerois (TG). As concentrações plasmáticas de LDL(-) dos participantes que tomaram ômega 3 apresentaram redução de 21%, enquanto que os que tomaram ômega 9 tiveram redução de 1%. Tal redução foi significativa em relação ao tempo de intervenção (p<0,05), mas não quando o efeito da internveção foi avaliado. Perfil semelhante foi observado para a razão LDL(-)/antiLDL(-), observou-se redução de 22% no grupo ômega 3 e redução de somente 3% no grupo ômega 9. Conclusão: A intervenção com ômega 3 promoveu redução na concentração plasmática de LDL(-), porém não modificou a concentração do anticorpo antiLDL(-) nem o tamanho das subfrações da LDL.Introduction: The Metabolic Syndrome (MetS) is a combination of factors that determine increased risk for Cardiovascular Diseases (CVD), mainly because of Insulin Resistance (IR) and the inflammatory state promoted by the hypertrophied white adipose tissue. Under this background, the dyslipidemic condition goes together with the developing of atherosclerosis, meaning that higher concentrations of low density lipoprotein (LDL) in plasma promote modifications from different sources in these particles and may have an impact over LDL subfractions, turning them more atherogenic. Omega three has proved hypolipidemic and anti-inflammatory effects, which may reduce cardiovascular risk in MetS individuals. Objetive: evaluate the effect of 3g of fish oil supplementation, 60% EPA and DHA during an eight week period over plasma concentrations of electronegative LDL particles [LDL(-)] and its antibodies, as well as monitoring possible changes in LDL subfractions. Methods: A total number of 115 participants, both sexes, between 30 and 74 years of age, with MetS, were included and separated in the intervention group receiving omega 3 (n=58) and the placebo group with omega 9 (n=57). Biochemical analyses were carried out using ELISA for LDL(-) and antiLDL(-) in plasma. Particle sizes were measured using the Lipoprint system. The effects of time and intervention were analyzed using the statistical program SPSS 20.0, assuming p<0.05 as significant. Results: Omega 3 supplementation had a significant effect in the reduction of fat mass percentage (FM%) and blood pressure, showing a 4% decrease for systolic and 5% decrease for diastolic pressures respectively. Considering the lipid profile, both interventions had significant effects reducing total cholesterol (TC), LDL-c, not HDL (nHDL) and tryacylglycerides (TG). LDL(-) plasma concentrations from the omega 3 group showed 21% reduction while the omega 9 group had only 1% reduction. Such difference was significant considering time (p<0,05), but not while comparing the intervention effect. There was also a change in the antiLDL(-) antibodies; reducing 2% in the omega 3 group and increasing 1% in the omega 9 group. However, those differences were not significant. Similar effects were observed in LDL(-)/antiLDL(-) ratio, showing 22% decrease in the omega 3 group and only 3% in the omega 9 group. Conclusion: Omega 3 intervention promoted a significant reduction in plasmatic LDL(-), however, it didn\'t modify LDL subfraction distribution.
13
Werutsky, Carlos Alberto. "As bases moleculares das hipercolesterolemias familiares no Brasil: o Rio Grande do Sul." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/17/17138/tde-01082007-105409/.
Full textAbstract:
A hipercolesterolemia familiar (HF) é uma doença autossômica dominante causada por mutações no gene do receptor de LDL (LDLR) (cromossomo 19p13.1 - p13.3), que alteram parcialmente ou totalmente a função do LDLR. A HF é também uma das doenças genéticas mais comuns com freqüências estimadas de heterozigotos e homozigotos de 1/500 e 1/1.000.000, respectivamente. Manifesta-se com altos níveis de LDL colesterol, arco corneal, xantomas tendíneos e sintomas prematuros de doença coronariana.. A grande heterogeneidade observada na manifestação clínica desta doença pode ser explicada, ao menos parcialmente, pelo amplo espectro de mutações no gene do LDLR. O presente estudo teve por objetivo a caracterização molecular do gene LDLR em pacientes com HF do Rio Grande do Sul (RS), Brasil. Para isso, foram obtidas amostras de DNA de 40 indivíduos provenientes de cinco macrorregiões do Estado, representando seis diferentes populações de ascendência européia, para a realização do seqüenciamento direto do gene do LDLR, com posterior análise por meio das ferramentas de bioinformática. Quinze mutações pontuais foram identificadas no gene do LDLR, a saber: c.408C>T (D115D), c.1616C>T (P518L), c.1773C>T (N570N) e c.2243A>G (D727G) na região codificadora, IVS6+36G>A, IVS6+171G>A, IVS11+56C>T, IVS11- 69G>T, IVS11-55A>C, IVS15-136A>G, IVS16+46C>T e IVS17-42A>G na região intrônica, e *52G>A, *105T>G e *141G>A na região 3\'-UTR. Destas, oito ainda não foram descritas na literatura (três situadas nos exons, quatro nos introns e uma na região 3\'-UTR). A mutação*52G>A foi previamente identificada em pacientes com HF da região Sudeste do Brasil, sugerindo que possa exercer um importante efeito na patogênese da HF em pacientes brasileiros. Em relação às macrorregiões do RS, os portugueses, italianos e espanhóis apresentaram o maior número de mutações dentre os grupos étnicos analisados. Assim, os resultados obtidos confirmam que existe um amplo de espectro de mutações no gene do LDLR. As mutações nas regiões intrônicas precisam ser investigadas sobre seu efeito potencial no desenvolvimento de HF. Considerando que este é o primeiro estudo que teve por objetivo a caracterização molecular de pacientes com HF no RS, novos estudos que visem a elucidação das bases moleculares da HF devem ser realizados, a fim de obter uma melhor caracterização genética desta doença no Brasil.Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in the low-density lipoprotein receptor (LDLR) gene (chromosome 19p13.1 - p13.3), which alter partially or totally the LDLR function. FH is also one of the most common inherited disorders with frequencies of heterozygotes and homozygotes estimated to be 1/500 and 1/1.000.000, respectively. Affected individuals display high levels of LDL cholesterol, arcus corneae, tendon xanthomas and premature symptomatic coronary heart disease. The extensive heterogeneity observed in the clinical manifestation of this disorder may be explained, at least partially, by the broad spectrum of mutations identified in the LDLR gene. The present study had as the main goal the molecular characterization of the LDLR gene in patients with FH from Rio Grande do Sul (RS) State, Brazil. For this, DNA samples were obtained from 40 individuals living in five macroregions of RS, representing six different isolated populations of European ascendancy. The LDLR gene was subjected to the direct sequencing with further analysis through bioinformatics tools. Fifteen punctual mutations were identified in the LDLR gene, namely: c.408C>T (D115D), c.1616C>T (P518L), c.1773C>T (N570N) and c.2243A>G (D727G) in the coding region, IVS6+36G>A, IVS6+171G>A, IVS11+56C>T, IVS11-69G>T, IVS11-55A>C, IVS15-136A>G, IVS16+46C>T and IVS17-42A>G in the intronic region, and *52G>A, *105T>G and *141G>A in the 3\'-UTR region. Of these, eight were not yet described in the literature (three situated in exons, four in introns and one in 3\'- UTR region). The *52G>A mutation was previously identified in FH patients from Southeast Brazil, suggesting that it can exert an important effect in the pathogenesis of FH in Brazilian patients. In relation to the macroregions of Rio Grande do Sul, Portuguese, Italian and Spanish subjects carried the highest number of mutations among the ethnic groups analyzed. Thus, the results obtained confirm the existence of a broad spectrum of mutations in the LDLR gene. The mutations in intronic regions need to be investigated in relation to its potential effect in the development of FH. Taking into account that this is the first study that had as the goal the molecular characterization of FH patients in RS, further studies aimed at elucidating the molecular bases of FH should be performed, in order to obtain the better characterization of this disease in Brazil.
14
Spessatto, Débora. "Associação dos níveis de HbA1c com colesterol LDL e colesterol LDL oxidado em indivíduos não-diabéticos." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2011. http://hdl.handle.net/10183/39649.
Full textAbstract:
Introdução: O Diabetes mellitus (DM) está associado a complicações crônicas micro e macrovasculares. A medida da hemoglobina glicada (HbA1c) avalia o grau do controle glicêmico em pacientes diabéticos e seus níveis são capazes de prognosticar o risco de desenvolvimento dessas complicações. Entre as origens das complicações causadas pela hiperglicemia, há a hipótese dos produtos finais de glicação avançada (AGEs) e do estresse oxidativo. A reação de glicação não enzimática das proteínas também está relacionada com as complicações diabéticas e é responsável pela formação da HbA1c. Entretanto, tem sido demonstrado um aumento dessa glicação em pacientes não diabéticos. Um dos prováveis mecanismos para esse aumento é a peroxidação lipídica, com conseqüente aumento nos níveis de malondialdeído (MDA) que modifica a apolipoproteína B (APO B) do colesterol de baixa densidade (LDL). A modificação oxidativa do LDL confere propriedades específicas pró-aterogênicas. A presença do LDL oxidado e o aumento da tendência do LDL à peroxidação lipídica, podem contribuir para o aumento dos níveis de HbA1c. Objetivo: Verificar a associação entre os níveis de HbA1c com o Colesterol LDL e LDL oxidado em Indivíduos não-diabéticos. Métodos: Foi realizado um estudo transversal observacional, no qual um total de 196 indivíduos, classificados como não-diabéticos, foram analisados e divididos em três grupos, conforme os valores de HbA1c e glicemia de jejum (GJ): Grupo 1 (n =64) - HbA1c <5,7% e GJ <100 mg/dL; Grupo 2 (n =69) - HbA1c ≥5,7 e ≤6,4% e GJ <100 mg/dL; Grupo 3 (n =63) - HbA1c ≥5,7 e ≤6,4% e GJ ≥100 e <126mg/dL. Amostras de sangue total e soro foram coletadas. O LDL oxidado foi medido por método imunoensaio enzimático (Mercodia ®), ApoB dosada por imunoturbidimentria, a relação Colesterol LDL(oxi)/Colesterol-HDL foi estimada, além das outras dosagens bioquímicas do perfil lipídico. Esses testes foram comparados e analisados entre os três diferentes grupos. Resultados: Houve diferença significativa nos níveis de LDL(oxi) (p< 0,001), Apo B (p= 0,026) e razão LDL(oxi)/HDL (p< 0,001) entre os três grupos. Os valores de HbA1c apresentaram correlação positiva com os valores de LDL (oxi) (r =0,431; p <0,001), LDL (r =0,148; p =0,039), Col Não-HDL (r =0,192; p =0,007) e Apo B (r =0,171; p <0,001). Estas associações positivas permaneceram significativas, mesmo após ajuste, por análise de regressão linear múltipla para as variáveis álcool, medicamentos, índice de massa corporal (IMC) e idade. Também apresentaram correlações positivas com os valores de HbA1c: razão LDL (oxi)/HDL (r =0,422; p <0,001), CT (r =0,142; p =0,048), triglicerídios (r =0,155; p =0,030) e IMC (r =0,263; p <0,001). Conclusão: Nosso estudo demonstrou associação dos níveis de HbA1c com as partículas lipídicas aterogênicas LDL, Apo B, colesterol não HDL e LDL (oxi). Os níveis de LDL, principalmente LDL (oxi), estão significativamente associados com os níveis de HbA1c e glicose, mesmo em indivíduos não-diabéticos. Os indivíduos classificados com alto risco de desenvolver DM ou DCV apresentam valores mais elevados de partículas de LDL oxidadas. Nossos dados sugerem que a presença de LDL (oxi) está relacionada com a glicação e ao aumento dos níveis sanguíneos de HbA1c em indivíduos não diabéticos.Background: Diabetes mellitus (DM) is associated with chronic microvascular and macrovascular complications. The measurement of glycated hemoglobin (HbA1c) assesses the degree of glycemic control in diabetics patients and their levels are able to predict the risk of developing these complications. The formation of advanced glycation and products (AGEs) and oxidative stress are some of the hypothesis described to explain the diabetic complications. The reaction of nonenzymatic glycation of proteins is also related to these complications and is responsible for the formation of HbA1c. However, it has been shown an increase in glycation in nondiabetic patients, which is maybe due to lipid peroxidation, consequently, the levels of malondialdehyde (MDA) increase and there is modifications in the apolipoprotein B (apoB) of low-density cholesterol (LDL). The oxidative modification of LDL confers specific proatherogenic properties. The presence of oxidized LDL and an increased tendency to LDL peroxidation contribute to increased levels of HbA1c in diabetic patients. Objective: To investigate the association between HbA1c levels and the levels of LDL cholesterol and oxidized LDL in subjects without diabetes. Methods: We conducted an observational cross-sectional study in which a total of 196 individuals, classified as non-diabetics, were analyzed and divided into three groups according to the values of HbA1c and fasting plasma glucose (FPG): Group 1 (n = 64) - HbA1c <5.7% and FPG <100 mg / dL, Group 2 (n = 69) - HbA1c ≥ 5.7 and ≤ 6.4% and FPG <100 mg / dL, Group 3 (n = 63) - HbA1c ≥ 5.7 and ≤ 6.4% and FPG ≥ 100 and <126mg/dL. Samples of whole blood and serum were collected. Oxidized LDL was measured by enzyme immunoassay method (Mercodia ®), ApoB was measured by imunoturbidimentria and the ratio LDL cholesterol (oxi) / HDL-cholesterol was estimated. Other biochemical measurements of lipid profile were also carried out. Results: There were significant differences in LDL (oxi) (p <0.001), Apo B (p = 0.026), and ratio LDL (oxi) / HDL (p <0.001) between the three groups. HbA1c values showed positive association with LDL (oxi) (r = 0.431, p <0.001), LDL (r = 0.148, p = 0.039), non-HDL Col (r = 0.192, p = 0.007) and Apo B (r = 0.171, p <0.001). These positive associations remained significant even after adjustment for multiple linear regression analysis for variables such as alcohol, drugs, BMI and age. The ratio LDL (oxi) / HDL (r = 0.422, p <0.001), CT (r = 0.142, p = 0.048), triglycerides (r = 0.155, p = 0.030) and BMI (r = 0.263, p <0.001) also showed positive correlations with HbA1c values. Conclusions: Our study demonstrated that there is association between HbA1c levels and the atherogenic lipid particles LDL, Apo B, non-HDL cholesterol and LDL (oxi). LDL levels, especially LDL (oxi), are significantly associated with HbA1c and glucose levels, even in non-diabetics. Individuals classified with high risk of developing diabetes or CVD have higher levels of oxidized LDL particles. Our data suggest that the presence of LDL (oxi) is related to glycation and increased blood levels of HbA1c in nondiabetic individuals.
15
Dehouck, Bénédicte. "Une nouvelle fonction du LDL récepteur : transcytose des LDL au travers de la barrière hémato-encéphalique." Lille 1, 1995. http://www.theses.fr/1995LIL10058.
Full textAbstract:
Les cellules endothéliales de capillaires cérébraux, support de la barrière hémato-encéphalique (BHE), présentent des caractéristiques morphologiques et biochimiques qui restreignent les échanges entre le sang et le cerveau. Le transport du glucose, des acides aminés, de l'insuline et d'autres molécules sont aujourd'hui connus. Par contre les modalités de transfert des lipides du sang au cerveau sont encore inconnues. Au contraire de l'endothélium des autres organes, l'endothélium des capillaires cérébraux présente un récepteur LDL. Nos travaux ont pour but d'étudier le rôle de ce récepteur. Ils sont effectués sur un modèle in vitro de BHE, consistant en une coculture de cellules endothéliales de capillaires cérébraux et d'astrocytes. Les études d'interactions entre ces deux types cellulaires montrent que lorsque les astrocytes sont déprimés en cholestérol, l'expression du récepteur LDL au niveau de l'endothélium cérébral est multipliée par 6. Cet effet est médié par un(des) facteur(s) soluble(s) exclusivement sécrété(s) par les astrocytes préalablement cultivés avec les cellules endothéliales cérébrales. Le facteur obtenu dans ces conditions permet l'induction du récepteur LDL au niveau d'autres cellules. Ces résultats montrent que le récepteur LDL au niveau de l'endothélium des capillaires cérébraux est l'une des caractéristiques de la BHE. L'étude du transport des LDL au travers de l'endothélium cérébral, montre que le transfert des LDL du sang vers le cerveau est spécifique et est inhibé par l'anticorps c-7 connu pour bloquer la fixation des LDL à leur récepteur. Ainsi le récepteur LDL au niveau de l'endothélium cérébral permet le transport des LDL au travers de la BHE. La transcytose des LDL est régulée en fonction des besoins lipidiques du parenchyme cérébral. Ces résultats confirment que la BHE est biologiquement active, et établissent un rôle nouveau du récepteur LDL, le transport des lipides au travers de la BHE.
16
Moorby, Catriona Deborah. "Regulation of the hepatic LDL receptor." Thesis, University of Cambridge, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386489.
Full text
17
Bremer, Sabine Carola. "In vivo Metabolismus von LDL-Subtypen bei Patienten mit koronarer Herzkrankheit und familiärer Hypercholesterinämie unter LDL-Apheresetherapie." Diss., lmu, 2006. http://nbn-resolving.de/urn:nbn:de:bvb:19-49288.
Full text
18
Ruiz, Jorge Luis Maria. "Caracterização de uma nanopartícula lipídica semelhante à LDL (LDE) como vetor para RNA de interferência." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5167/tde-14062011-154226/.
Full textAbstract:
As nanopartículas são consideradas promissores vetores para a liberação eficaz e segura de ácidos nucléicos para tipos específicos de célula ou tecido, proporcionando uma alternativa aos vetores virais para terapia gênica. No entanto, com a maioria destes sistemas não torna possível a entrega de oligonucleotídeos nas células in vivo de forma especifica. O uso de uma nanoemulsão funcionalmente semelhante à lipoproteina de baixa densidade poderia resolver esse problema, pois esta particula é capaz de direcionar o transporte das moléculas para a internalização celular através de receptores de LDL. Aqui, descreve-se um sistema lipidico semelhante à lipoproteína de baixa densidade, LDE, capaz de direcionar e liberar RNA de interferência (RNAi) para as células tumorais in vitro e in vivo em um modelo celular que expressa resistência a múltiplas drogas (células de sarcoma uterino; MESSA/ Dx5). Estudou-se também as caracteristicas de captação do complexo LDE-RNAi e a regulação especifica do gene mdr-1. Os resultados sugerem que a LDE é estavel e liga-se com alta afinidade aos RNAis permitindo que eles entrem nas células tumorais, com localização citoplasmática. Em conclusão, a LDE, por direcionar o RNAi a receptores de LDL favorece o silenciamento do gene mdr-1 por RNAi nas células MES-SA/Dx5 aumentando sua sensibilidade a quimioterápicosNanoparticles are considered promising vectors for efficient and safe delivery of nucleic acids to specific types of cell or tissue, providing an alternative to viral vectors for gene therapy. However, most of these systems cannot target and deliver oligonucleotides to specific cells in vivo. The use of nanoemulsion functionally resemble low density emulsion could solve this problem, once particle is capable of direct the molecules transport to the cell through internalization in LDL receptors. Here, we describe a lipid system similar to low density lipoprotein, LDE, capable of targeting and release small interfering RNA (siRNA) to tumor cells in vitro and in vivo in a cell model that expresses multidrug resistance (sarcoma uterine cell line; MES-SA/Dx5). Were also studied the characteristics of uptake of the complex LDE-siRNA, as well as the downregulation of mdr-1 gene. The results suggest that LDE is stable and bind with high affinity to siRNAs allowing them to enter tumor cells, with cytoplasmic localization enhanced. In conclusion, LDE, binds to siRNA through LDL receptors, and promotes mdr-1 silenciament by RNAi in MES-sa/Dx5 cells, increasing their sensitivity to chemotherapeutics agents
19
Kader, Abdul. "Delivery of cytotoxic agents using low density lipoprotein (LDL) : physico-chemical and biological evaluation of LDL-drug conjugates /." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/MQ54900.pdf.
Full text
20
Santos, Andreza Oliveira dos [UNIFESP]. "Relação entre os títulos de anticorpos anti LDLox e marcadores do risco cardiovascular." Universidade Federal de São Paulo (UNIFESP), 2008. http://repositorio.unifesp.br/handle/11600/10030.
Full textAbstract:
Made available in DSpace on 2015-07-22T20:50:43Z (GMT). No. of bitstreams: 0
Previous issue date: 2008-11-26Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Objetivos: As lipoproteínas oxidadas e os anticorpos anti-LDL oxidada (anti-LDLox) têm sido detectados no plasma e em lesões ateroscleróticas em humanos. No entanto, o papel destes autoanticorpos na proteção vascular ou na patogênese das síndromes coronarianas agudas (SCA) permanece não elucidado. Nós examinamos a relação entre os títulos de IgG humana anti-LDLox com marcadores de risco para a doença cardiovascular. Métodos: Títulos de autoanticorpos anti-LDLox foram mensurados em indivíduos portadores de hipertensão arterial em estágio 1 (n=94), sem outros fatores de risco, e em indivíduos com síndrome metabólica após recente síndrome coronariana aguda (n=116). Os autoanticorpos contra a LDL oxidada pelo cobre foram avaliados por ELISA. Resultados: pacientes com hipertensão arterial apresentaram menor índice de massa corpórea e circunferência abdominal, maiores níveis de pressão arterial sistólica e diastólica quando comparados aos portadores de SCA (p<0,001). O HDL-C e a Apo A1 foram maiores, enquanto os triglicérides e a Apo B foram menores nos pacientes do grupo hipertensão em estágio 1 (p<0,0001). Os títulos de anticorpos anti-LDLox foram maiores no grupo hipertensão comparados aos do grupo SCA, e os hipertensos do primeiro grupo apresentaram níveis de PCR menores do que indivíduos com SCA (p<0,0001). A análise conjunta de ambos os grupos mostrou, em análise univariada, significante correlação inversa para a PCR (r=-0,284), IMC (r=-0,256), circumferência abdominal (r=-0,368), apo B (r=-0,191) e glicemia (r=-0,303) e correlações positivas entre pressão arterial sistólica e diastólica (r=0,319 e r=0,167, respectivamente), HDL-C e Apo A1 (r=0,224 e r=0,257, respectivamente), com os títulos de anticorpos anti-LDLox (p<0,02). Regressão linear múltipla mostrou que a PCRas, glicemia e circunferência abdominal permaneceram independente e negativamente associados com os títulos de anticorpos anti-LDLox. Conclusões: nossos resultados sugerem que os títulos baixos de anticorpos circulantes anti-LDLox possam estar associados com maior risco cardiovascular.
Objectives: Oxidized lipoproteins and antibodies anti-oxidized LDL (anti-oxLDL) have been detected in human plasma and in atherosclerotic lesions. However, the role of these autoantibodies in the maintenance of health or in the pathogenesis of acute coronary syndromes (ACS) remains unclear. We examined the relationship of human IgG antibodies anti- ox LDL with cardiovascular disease risk markers. Methods: Titers of human anti-oxLDL were measured in hypertensive subjects in stage 1 (n=94) without other risk factors, and in individuals with metabolic syndrome after recent acute coronary syndrome (n=116). Autoantibodies against copper ion oxidized LDL were measured by ELISA. Results: Hipertensive patients presented lower BMI, waist circunference, higher blood pressure levels than those with ACS (p<0.001). HDL-C and Apo A1 were higher, whereas triglycerides and Apo B were lower in those with hypertension stage 1 (p<0.0001). Anti-oxLDL titers were higher in hypertensive patients compared to those with acute coronary syndromes, and hypertensive patients presented lower hs-CRP than those with ACS (p<0.0001). Taken into account both populations, univariate analysis showed small, but significant inverse correlations between the hs-CRP (r=-0.284), BMI (r=-0.256), waist circunference (r=-0.368), apo B (r= -0.191), and blood glucose (r= - 0.303) and positive correlations between systolic and diastolic blood pressure (r=0.319 and r=0.167, respectively), HDL-C and Apo A1 (r=0.224 and r=0.257, respectively), with anti-ox LDL titers (p<0.02). After multiple linear regression, hs-CRP, fasting glycemia and waist circunference remained independently associated with anti-oxLDL. Conclusions: Our results suggest that low titers of circulating anti-oxLDL antibodies may be associated with increased cardiovascular risk.
TEDE
BV UNIFESP: Teses e dissertações
21
McPherson, Katrine L. "Effects of LDL cholesterol on vascular function." Thesis, University of Glasgow, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321719.
Full text
22
Sanan, David Austin. "Receptor-mediated endocytosis of low density lipoproteins in aortic endothelial cells." Doctoral thesis, University of Cape Town, 1986. http://hdl.handle.net/11427/27208.
Full textAbstract:
Lipoprotein binding and metabolism in actively-dividing (subconfluent) and quiescent (postconfluent) bovine aortic endothelial cells (ECs) were qualitatively investigated by fluorescence microscopy using dioctadecylindocarbocyanine-labelled lipoproteins and by indirect immunofluorescence microscopy. LDL and acetylated-LDL (AcLDL) were seen bound to the surfaces of subconfluent ECs (at 4°C or at 37°C), as a random distribution of punctate foci. ECs therefore closely resembled fibroblasts in the distribution of LDL receptors on their surfaces. No binding of LDL was seen on postconfluent EC surfaces by either direct or indirect fluorescence microscopy. The patterns of AcLDL binding on postconfluent ECs resembled those on subconfluent ECs. Intracellular LDL and AcLDL occurred as perinuclear accumulations of large fluorescent disc-shaped profiles in subconfluent ECs. These accumulations were shown to arise from surface-bound material by pulse-chase experiments. Intracellular LDL was absent in the majority of postconfluent ECs, while AcLDL accumulation was massive. "Wounding" of cultures allowed simultaneous assessment of lipoprotein metabolism in quiescent and actively-dividing areas of the same culture. Quantitative assessments of the above-mentioned phenomena were made using ¹²⁵I-labelled lipoproteins. Receptor-mediated binding of LDL decreased five to ten-fold as the cultures modulated from subconfluent to postconfluent morphology. No receptor-bound LDL was detected in postconfluent ECs. Conversely, the amount of AcLDL bound increased at least fivefold during EC growth in parallel cultures. The amounts of lipoproteins endocytosed and metabolised were generally related proportionately to the amounts bound in each case. The distribution of LDL receptors on cultured cells was also investigated at the ultrastructural level using colloidal gold-conjugated LDL as a probe, and similarly labelled antibodies as probes. Whole-mounted cells with receptor probes bound to them were examined directly in the transmission electron microscope. The topographical distribution of LDL receptors has not been investigated by these techniques before. A novel method of preparing cytochemically-labelled, whole-mounted cells from styrene culture dishes was developed and used in this study. LDL Receptors expressed on the surfaces of human skin fibroblasts served to standardise these colloidal gold techniques and fortuitously led to new information on receptor distribution. Normal (FGo) and LDL receptor-negative mutant fibroblasts (GM 2000) acted as positive and negative controls respectively. Normal fibroblast LDL receptors were grouped into clusters consistent in size with coated pits (200 - 500 nm in diameter). A novel finding was the presence of a diffuse population of receptors scattered randomly amongst the clustered receptors. Another mutant fibroblast, GM 2408A, known to have an aberrant LDL receptor distribution, was also examined. Its receptors were shown to be dispersed singly, and in occasional groups of two and three, at random over the cell surfaces. No clusters were detected. The receptor-negative GM 2000 bound virtually no probes. While not as sensitive as the colloidal gold-conjugated LDL probe, an antireceptor monoclonal antibody (IgG-C7), localised by indirect immunogold labelling, gave similar results when applied to the above cells. This was taken as strong corroborative evidence that the LDL receptor distributions as determined by colloidal gold-conjugated LDL were correct. It is suggested that the dispersed population of receptors on normal fibroblasts may represent newly-emerged recycling receptors which have yet to cluster in coated pits. A further new finding reported here is the existence of the same two patterns of LD L receptors, dispersed and clustered, on the surface of subconfluent ECs. It was noted, from the study of whole-mounted and thin-sectioned cells, that the receptors were preferentially arranged in rings following the circumference of coated pit areas on the cell surface. Often these rings associated in groups or even coalesced into compound clusters. The significance of these groupings is not yet understood. In sharp contrast to the situation on subconfluent ECs, no LDL receptors (probed with the extremely sensitive colloidal-gold conjugated LDL) could be detected at the EM level on the surface of postconfluent ECs. Active cells in wounded postconfluent monolayers expressed abundant receptors detected at the EM level. It is concluded that postconfluent quiescent bovine aortic ECs in vitro metabolise virtually no LDL via the LDL-receptor pathway due to a vanishingly low number of LDL receptors. This contrasts with the ability of postconfluent cells to metabolise relatively large amounts of AcLDL via a receptor-mediated mechanism. The significance of these conclusions is discussed with respect to the interaction of plasma lipoproteins with the endothelium in vivo.
23
Cavalcante, Luciana da Silveira. "Otimização e aplicação da quantificação do colesterol da lipoproteína de baixa densidade pequena e densa (sd-LDL-C)." Florianópolis, SC, 2011. http://repositorio.ufsc.br/xmlui/handle/123456789/95730.
Full textAbstract:
Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde. Programa de Pós-Graduação em FarmáciaMade available in DSpace on 2012-10-26T05:24:48Z (GMT). No. of bitstreams: 1 289967.pdf: 1658757 bytes, checksum: 5a241699e8a8e7cfa5d6aaf3d0453fb8 (MD5)
24
AGNANI, GENEVIEVE. "Interactions de ligands du recepteur ldl avec differents types cellulaires : etude d'un anticorps-recepteur ldl, etude de particules lipoproteiniques." Lille 2, 1989. http://www.theses.fr/1989LIL2P261.
Full text
25
Favero, Giovani Marino. "Nanoemulsão contendo 7-cetocolesterol (LDE/7KC) promove inibição do crescimento de melanoma em camundongos e aumento de sobrevida." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/5/5146/tde-12062007-100409/.
Full textAbstract:
7-cetocoleterol (7KC) é um oxisterol conhecido por inibir a proliferação celular e por ser citotóxico. Desenvolvemos uma nanoemulsão contendo 7KC (LDE/7KC) que demonstrou efeito anti-proliferativo sobre as linhagens RPMI 8226 (mieloma) e melanoma (B16F10), in vitro, sendo preferencialmente captada via receptores de LDL. No presente trabalho avaliamos, in vivo, a cinética plasmática, biodistribuição, ação anti-tumoral e parâmetros tóxico-hematológicos em camundongos portadores de melanoma. A cinética plasmática apresentou um decaimento estatisticamente igual entre os animais portadores de melanoma e não portadores. Em relação à biodistribuição da nanoemulsão, houve um acúmulo de seus componentes radioativamente marcados, principalmente no fígado e no tumor, sugerindo sua captação via receptores de LDL. LDE/7KC promoveu uma redução superior a cinqüenta por cento do tamanho do tumor, que apresentou maior área de necrose e menor quantidade de vasos. Nos camundongos tratados com LDE/7KC houve um aumento da sobrevida. As análises toxico-hematológicas demonstraram que a nanoemulsão apresentou pouca ou nenhuma toxicidade. Os resultados demonstram a possibilidade da utilização da nanoemulsão LDE/7KC como um agente no tratamento do câncer, com poucos efeitos colaterais, devido a sua seletividade aos receptores da LDL.7-ketocholesterol (7KC) is an oxysterol known to inhibit cell proliferation and to be cytotoxic. A nanoemulsion containing-7KC (LDE/7KC) was shown to have antiproliferative effects on RPMI 8226 myeloma cell line and melanoma (B16F10), in vitro. This particle is taken up mainly by LDL receptors. Here we have evaluated the plasma kinetic, biodistribution, anti-tumoral action and hematologic toxicity of LDE/7KC in melanoma bearing mice. The nanoemulsion accumulated in the liver and tumor, tissues with a high expression of LDL receptors. LDE/7KC promoted a tumor size reduction over fifty percent. An increased necrosis area and a decreased amount of blood vessels were found. An increased survival rate was observed. The hematolgic analyses demonstrated a lack of toxicicity. The results shows the possibility to use the LDE/7KC nanoemulsion as an agent for cancer treatment, with few collateral effects probably due to its internalization by LDL receptors.
26
Bonfleur, Maria Lúcia. "Efeito da hipercolesterolemia genetica sobre a homeostase glicemica e secreção de insulina em camundongos knockout para o recptor de LDL ('LDLR POT. -/-')." [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314760.
Full textAbstract:
Orientadores: Helena Coutinho Franco de Oliveira, Antonio Carlos BoscheroTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
Made available in DSpace on 2018-08-08T19:29:15Z (GMT). No. of bitstreams: 1 Bonfleur_MariaLucia_D.pdf: 1633140 bytes, checksum: 765548b2268a05188490bc90cf1939b8 (MD5) Previous issue date: 2007
Resumo: Neste trabalho, investigamos se a hipercolesterolemia primária per se, independente de dieta rica em gordura, afeta a homeostase glicêmica e a secreção de insulina estimulada por vários secretagogos em animais knockout para o receptor de LDL (LDLR-/-). Além disso, investigamos os possíveis mecanismos envolvidos na liberação deste hormônio neste modelo animal. Podemos resumir nossos achados da seguinte maneira: camundongos LDLR-/- apresentam hiperglicemia pós-prandial, hipoinsulinemia, intolerância à glicose e sensibilidade periférica à insulina normal. Nós demonstramos que, as alterações na homeostase glicêmica ocorrem em parte, por uma diminuição da sensibilidade das ilhotas à glicose. A secreção de insulina é normal na presença de baixa concentração de glicose, entretanto na presença de 11,1 mmol/l, as ilhotas de animais LDLR-/- liberam menos insulina que as ilhotas controles. A secreção de insulina estimulada por outros secretagogos metabolizáveis (leucina e KIC) também está reduzida nas ilhotas dos animais knockout. O conteúdo total de insulina e DNA são similares entre os grupos, sugerindo que as alterações na secreção de insulina não ocorrem devido a diferenças no tamanho e/ou número de células b. Observamos uma redução na primeira e segunda fase de secreção de insulina estimulada por 11,1 mmol/l de glicose. A oxidação da glicose está reduzida, enquanto a metabolização da leucina está aumentada. Quando adicionamos agentes despolarizantes (KCl, Arginina e Tolbutamida), observamos uma redução da secreção de insulina tanto em concentrações basais quanto estimulatórias de glicose. Na presença de 11,1 mmol/l de glicose e carbacol (agonista colinérgico) ou PMA (ativador da proteína-quinase C), a secreção de insulina foi semelhante entre os grupos LDLR- /- e controles. Entretanto, quando estimulamos a secreção com forskolin ou IBMX, que aumentam os níveis de AMPc, observamos redução na liberação de insulina pelas ilhotas dos animais LDLR-/- em comparação com os controles. A expressão protéica da fosfolipase C (PLCb2) está aumentada enquanto que a expressão da proteína-quinase A (PKA) está reduzida nas ilhotas dos animais LDLR-/-. Assim, observamos que camundongos LDLR-/- apresentam alterações na homeostase glicêmica independente de dieta rica em gordura, provocada por redução na secreção de insulina devido, em parte à redução do metabolismo da glicose, bem como, redução na expressão da PKA
Abstract: In this work, we investigated whether primary hyperlipidemia per se, independently of a high-fat diet, affects glycemia and insulin secretion stimulated by several secretagogues in hypercholesterolemic low-density lipoprotein receptor knockout mice (LDLR-/-). In addition, we investigated the possible mechanisms involved in the release of this hormone. We found that, besides higher total cholesterol and triglyceride plasma concentrations, glucose plasma levels were increased and insulin decreased in LDLR-/- compared to the wild type (WT) mice. LDLR-/- mice presented impaired glucose tolerance, but normal whole body insulin sensitivity. In addition, we also demonstrate that the main cause of the impaired glucose homeostasis is a reduced pancreatic islet insulin secretion ability following fuel secretagogue stimuli. LDLR-/- mice have impaired insulin secretion in response to glucose without alterations in the pancreatic total insulin and DNA contents. These findings support the idea that the decreased response to glucose cannot be explained by differences islet size or number of beta cells, but it is probably caused by a defect in the secretory process. Glucose oxidation was 30% lower and L-leucine oxidation 60% higher in LDLR-/- islets than in WT islets. At basal (2.8 mmol/l) and stimulatory (11.1 mmol/l) glucose concentrations, the insulin secretion rates induced by depolarizing agents such as KCl, L-arginine and tolbutamide were significantly reduced in LDLR-/- when compared with WT islets. Insulin secretion induced by the PKA activators, forskolin and IBMX, in the presence of 11.1 mmol/l glucose, was lower in LDLR-/- islets, and it was normalized in the presence of the PKC pathway activators, carbachol and PMA. Western blotting analysis showed that phospholipase C-b2 expression was increased and PKA-a decreased in LDLR-/- compared with WT islets. In conclusion, we demonstrate that genetic hypercholesterolemia, due to complete deficiency of LDLR, impairs the beta cell insulin secretion, leading to hyperglycemia without affecting body insulin sensitivity. The lower insulin secretion in LDLR-/- mice islets may be explained by reduced glucose metabolism and expression of PKA
Doutorado
Fisiologia
Doutor em Biologia Funcional e Molecular
27
Kaščáková, Slávka. "The study of the interaction between hypericin and low-density lipoproteins (LDL) : the effect of the LDL receptors on the accumulation of the complex hypericin/LDL in glioma cells U-87 MG." Université d’Orléans, 2007. http://www.theses.fr/2007ORLE2081.
Full textAbstract:
L'internalisation et la distribution subcellulaire des photosensibilisateurs (pts) sont des paramétres critiques dans l'efficacité des thérapies photodynamiques. Les LDL font parti des transporteurs naturels les plus importants des pts hydrophobiques. L 'Hypéricine (Hyp) est un pigment photosensible et naturelle. En raison de son caractère, l 'Hyp peut interagir avec les LDL et être spécifiquement vectorisée vers les cellules. Nous montrons par spectroscopie d'absorbance et de fluorescence que l'Hyp interagit avec les LDL sous forme monomérique pour des ratios de concentration Hyp/LDL inférieurs à 30: 1. Des ratios supérieurs conduisent à la formation d'agrégats d'Hyp dans les LDL ce qui se traduit par les quenching statique et/ou dynamique de la fluorescence de l'Hyp. Nous montrons que la photoactivation de l'Hyp induit l'oxydation des LDL. Le niveau d'oxydation maximal étant atteint pour un ratio Hyp/LDL = 30 :1. L'implication des récepteurs aux LDL dans l'internalisation de l'Hyp par des cellules U-87 MG a être évaluée. Nos résultats indiquent que la concentration d'Hyp dans les cellules est influencé par la composition du milieu de culture. D'autre part, la concentration d'Hyp dans les cellules cultivée avec des LDL est proportionnelle au ratio Hyp/LDL. De plus, une augmentation importante de l'internalisation de l'Hyp a été correlée avec la surexpression des récepteurs aux LDL. Enfin, nous montrons que l'Hyp internalisée se concentre dans les lysosomes et sa quantité augmente avec le nombre de récepteurs aux LDL lorsque le milieu de culture contient des LDL. Ces résultats suggère que la voie d'internalisation des LDL est essentielle à l' accumulation d'Hyp dans les cellulesThe incorporation and subcellular localization of photosensitizers (pts) are critical determinants of their efficiency in photodynamic therapy. The most important transporters of hydrophobie pts are low-density lipoproteins (LOL). Hypericin (Hyp) is a natural photosensitizing pigment. According to character of Hyp and possibility of its specific targeting into cells through LDL, the study of •. Interaction of Hyp with LDL is important. By means of absorption and fluorescence spectroscopy we showed, that Hyp binds to LOL as monomers up to concentration ratio Hyp/LDL = 30:1. Further increasing ofHyp concentration leads to the formation of Hyp aggregates inside LDL and/or dynamic self-quenching of Hyp. We demonstrated that photoactivated Hyp oxidizes LDL. The maximum of the oxidation of LDL by Hyp is achieved for ratio Hyp/LDL = 30: 1. For higher ratio a decrease in the oxidation of LDL was observed. Further the dependence of the uptake of Hyp by U-87 MG cells on the level of expression of LDL receptors was studied. The results show that the composition of incubation medium influences the concentration of Hyp in cells. The intracellular concentration of Hyp in the presence of LDL is proportional to the Hyp/LDL ratio. A role of LDL receptor pathway for Hyp delivery to cells was confinned by the increase of Hyp uptake in the presence ofLDL for the higher number of LDL receptors. The co-localization experiments showed the lysosomal localization of Hyp with enhanced Hyp concentration for cells with elevated number of LDL receptors when LDL was used as transporters. Our results suggest that LDL and its pathway play an important role in the Hyp delivery and accumulation into the cells
28
Ozinsky, Adrian. "Post-translational processing of the low density lipoprotein receptor." Doctoral thesis, University of Cape Town, 1996. http://hdl.handle.net/11427/26672.
Full textAbstract:
The low density lipoprotein (LDL) receptor is a transmembrane glycoprotein that mediates the uptake of plasma LDL and thereby provides cholesterol to cells. During its synthesis in the endoplasmic reticulum, the LDL receptor folds and forms disulfide bonds in multiple cysteine-rich repeats. N- and 0-linked oligosaccharide chains are added in the endoplasmic reticulum and processed during passage through the Golgi apparatus, en route to the cell surface. The aim of this thesis was to study the influence of post-translational events on the synthesis of the LDL receptor. Experiments addressed: 1) the necessity of the compartmental organisation of the secretory pathway for the glycosylation of the LDL receptor; 2) the requirements for the formation of disulfide bonds; 3) the role for the chaperone, calnexin, in the folding of the LDL receptor; and 4) the manner in which folding was disrupted by mutations. Experiments were performed in cultured cells that were incubated with [³⁵S]methionine. Biosynthetically-labelled LDL receptor was immunoprecipitated and was analysed by SOS polyacrylamide gel electrophoresis.
29
Silaste, M. L. (Marja-Leena). "Dietary effects on antioxidants, oxidised LDL and homocysteine." Doctoral thesis, University of Oulu, 2003. http://urn.fi/urn:isbn:9514270703.
Full textAbstract:
Abstract
Dietary vegetables and fruit may play a significant role in atherosclerosis. We investigated the effects of a high intake of vegetables, berries, and citrus fruit along with a diet low in total and saturated fat on plasma concentrations of lipids, lipoprotein(a), antioxidants, oxidised LDL (OxLDL), folate, homocysteine, and on serum paraoxonase-1 activity. We also determined whether gene polymorphisms affect diet response of plasma homocysteine and serum paraoxonase-1 activity. Thirty-seven healthy females consumed two diets (low and high vegetable diets) in a controlled crossover intervention. The plasma measurements were determined at the baseline and at the end of diet periods.
The average plasma concentrations of total, LDL, and HDL cholesterol were 5.0 mmol/l, 2.8 mmol/l, and 1.7 mmol/l, respectively, on the low vegetable diet, and decreased by 8%, 8%,and 5%, respectively, in response to the high vegetable diet. The high vegetable diet increased the plasma concentrations of alpha-carotene, beta-carotene, lutein-zeaxanthin, beta-cryptoxanthin, and vitamin C by 133%, 134%, 107%, 65%, and 25%, respectively, compared with the low vegetable diet. There were no differences in the plasma concentrations of OxLDL between the low and high vegetable diets. The mean serum paraoxonase-1 activity was lower at the end of the high vegetable diet (226 U/l) than at the end of the low vegetable diet (240 U/l). Subjects having a genotype with high baseline paraoxonase-1 activity showed the most extensive reduction in their serum enzyme activities.
The high vegetable diet enhanced the serum and erythrocyte folate concentrations by 78% and 14%, respectively, and reduced the plasma homocysteine by 13% compared with the low vegetable diet. The dietary treatment was effective even among subjects homozygous for C677T mutation in methylenetetrahydrofolate reductase gene, who are susceptible to high homocysteine levels.
In conclusion, a high intake of vegetables, berries, and citrus fruit resulted in reduced plasma total and LDL cholesterol concentrations and enhanced plasma antioxidant levels. The high vegetable diet also effectively increased blood folate concentrations and reduced plasma homocysteine concentration.
30
Dolley, Guillaume. "La génétique des particules LDL petites et denses." Thesis, Université Laval, 2011. http://www.theses.ulaval.ca/2011/27881/27881.pdf.
Full text
31
Crabtree, Elaine. "The role of metal ions in LDL peroxidation." Thesis, Birkbeck (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266211.
Full text
32
Yoshida, Hiroyuki. "Compensated endocytosis of LDL by hamster cells co-expressing the two distinct mutant LDL receptors defective in endocytosis and ligand binding." Kyoto University, 1999. http://hdl.handle.net/2433/181746.
Full text
33
Pires, Luis Antonio. "Uso de emulsão lipídica como veículo do paclitaxel na terapia sistêmica do carcinoma da mama." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/5/5139/tde-23112006-105415/.
Full textAbstract:
INTRODUÇÃO: Estudos mostraram que, após a injeção de LDE na corrente sangüínea de mulheres portadoras de câncer de mama, ela encontra-se mais concentrada em tecido neoplásico que no tecido normal. Recentemente, estudos pré-clínicos comprovaram que a associação LDE-oleato de paclitaxel é estável, menos tóxica e com mais atividade terapêutica quando comparada ao uso de paclitaxel comercial em animais. O presente estudo teve como objetivo verificar a estabilidade dessa associação na circulação, a sua capacidade em se concentrar no tecido neoplásico e determinar os parâmetros farmacocinéticos em relação ao paclitaxel isolado. MÉTODOS: Para determinar os parâmetros farmacocinéticos foram administrados, por via intravenosa, [3H]-oleato de paclitaxel associado a [14C]- oleato de colesterol-LDE em três pacientes e [3H]-paclitaxel comercial em duas pacientes 24 horas antes do procedimento cirúrgico. Todas as pacientes eram portadoras de neoplasia maligna da mama. Amostras de sangue foram colhidas durante 24 horas. A radioatividade foi medida por cintilação líquida e os parâmetros farmacocinéticos foram calculados usando um modelo multicompartimental. Fragmentos de tecido neoplásico e de tecido normal mamário foram coletados durante a cirurgia e submetidos à contagem radioativa. RESULTADOS: As taxas fracionais de remoção da LDE e do oleato de paclitaxel foram semelhantes (0,0296 ± 0,0264 e 0,0182 ± 0,0186, respectivamente, p = 0,5742). A captação tanto da LDE quanto do oleato de paclitaxel mostrou concentração 2,5 a 3 vezes maior no tecido tumoral do que no tecido mamário normal. O tempo de meia vida do oleato de paclitaxel foi maior do que o da formulação comercial (18,97 ± 7,7 horas e 7,34 ± 0,40 horas) e, a depuração plasmática, menor (1,51 ± 0,18 (L/h) e 7,95 ± 4,32 (L/h)). CONCLUSÃO: A maior parte do fármaco ficou retido na microemulsão até sua remoção da circulação e captação pelas células. O oleato de paclitaxel associado à LDE mostrou-se estável na circulação sangüínea e apresentou tempo de meia vida maior e a depuração plasmática menor do que a formulação comercial, além de se concentrar mais no tecido neoplásico da mama. Os resultados permitem sugerir que essa associação pode se constituir em uma estratégia útil no tratamento de mulheres portadoras de câncer da mama.INTRODUCTION: Studies had shown that, after the injection of LDE in the circulation of women with breast cancer, it was more concentrate in neoplastic tissue that in the normal tissue. Recently, studies had proven that the LDE-paclitaxel oleate association is steady, less toxic and with more therapeutical activity when compared with the commercial paclitaxel in animals. The present study was designed to verify the stability of this association in the circulation, its capacity in concentrating in the neoplastic tissue and to determine the plasma kinetics of the association compared to that of paclitaxel isolated. METHODS: To determine the pharmacokinetic parameters, [3H]-paclitaxel oleate associated to LDE labeled with [14C]-cholesterol oleate was intravenously injected into three patients and [3H]-commercial paclitaxel into two patients 24 hours before the surgical procedure. All the patients had breast cancer. Blood samples were collected during 24 hours. Radioactivity was quantified in a scintillation solution and the pharmacokinetic parameters were calculated by compartmental analysis. Specimens of tumoral and normal breast were excised during the surgery and submitted to a radioactive counting. RESULTS: Fractional clearance rate of LDE and of the paclitaxel oleate were similar (0,0296 ± 0,0264 and 0,0182 ± 0,0186, respectively, p = 0,5742). The uptake of both [14C]-LDE and [3H]-paclitaxel oleate by breast malignant tissue was two and three fold greater than that of the normal breast tissue. The paclitaxel oleate plasma half-life (h) was greater than the commercial paclitaxel (T1/2 = 18,97 ± 7,7 and 7,34 ± 0,40) and the total plasma clearence (L/h) of paclitaxel oleate was lesser than the commercial (CL = 1,51 ± 0,18 and 7,95 ± 4,32). CONCLUSION: Most of the drug was restrained in the microemulsion until its removal from the circulation and captation by the cells. The paclitaxel oleate associated to LDE is stable in the bloodstream and has greater plasma half-life and lesser clearence than those for commercial paclitaxel. In addition, the association could be concentrated more in malignant breast tissue. The results allow to suggest that this association can consist in a useful strategy in the treatment of women with breast cancer.
34
Casciola, Livia Angela Flavia. "The cellular degradation of the low density lipoprotein receptor and its ligand." Doctoral thesis, University of Cape Town, 1987. http://hdl.handle.net/11427/27207.
Full textAbstract:
The cellular degradation of the low density lipoprotein (LDL) receptor, and its ligand, LDL, were investigated in order to clarify certain mechanistic aspects of these important processes. Long-term lymphoblastoid cell lines and cultured human skin fibroblasts were used to examine the fate of ¹²⁵I-LDL subsequent to its uptake via receptor-mediated endocytosis. In both cases, binding activity was saturable, depended on the presence of calcium ions in the medium, and was calculated to have an equilibrium dissociation constant at 4ᵒC of 2 μg ¹²⁵I-LDL/ml. No high-affinity binding was detected when the ligand was modified by acetylation. After incubating the monolayers at 37°C LDL/LDL receptor complexes were internalized, and the receptors were recycled back to the surface within about 10 minutes. Apolipo-protein B in the LDL particles was largely degraded to the amino acid level: chloroquine, a lysosomotropic agent, inhibited the formation of the ¹²⁵I-LDL degradation products. Cells obtained from a number of heterozygous and homozygous familial hypercholesterolemic patients, as expected, bound markedly reduced amounts of ligand. The half-life of ¹²⁵I-LDL was measured after it had been introduced into cultured fibroblasts by one of the following processes: (i) uptake via receptor-mediated endocytosis in human skin fibroblasts with normal LDL receptors, or (ii) incorporation via scrape-loading into fibroblasts defective in LDL receptor content. The half-lives obtained were about 1 hour and 50 hours, respectively, indicating that efficient degradation of LDL occurred only when it was deIivered to lysosomes via receptor-mediated endocytosis.
35
Grewe, Nicole. "Einfluss einer Virusdosiseskalation beim adenoviralen LDL-Rezeptorgentransfer im Kaninchenmodell." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=97650930X.
Full text
36
Seldte, Jens-Paul. "Lipoproteinprofil und Oxidierbarkeit von LDL vor und nach Ausdauertraining." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=964694441.
Full text
37
Gibson, A. W. "The role of the reticuloendothelial system in LDL metabolism." Thesis, University of Glasgow, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381452.
Full text
38
Svensson, Henrik. "Ldl-sänkande läkemedelsbehandling för hjärtinfarktpatienter - är nuvarande behandlingsriktlinjer rimliga?" Thesis, Linnéuniversitetet, Institutionen för kemi och biomedicin (KOB), 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-74501.
Full textAbstract:
Sammanfattning Bakgrund Insjuknande i hjärtinfarkt har minskat kraftigt i Sverige de senaste åren men drabbar fortfarande många. Ateroskleros i hjärtats kranskärl är den viktigaste bakomliggande orsaken. Utvecklingen av ateroskleros sker under lång tid och processen är komplex men kan kopplas till inflammatoriska processer, apoB-innehållande lipoprotein och endoteldysfunktion. LDL bedöms av många forskare vara en kausal faktor vid aterosklersutvecklingen. Denna bedömning grundar sig på djurförsök, observationsstudier, resultat från kliniska prövningar med LDL-sänkande läkemedel samt mendelska randomiseringsstudier. Behandlingsrekommendationerna vid sekundärprevention av hjärtinfarktpatienter innefattar behandling med hög dos statin där vissa av rekommendationerna sätter upp ett mål på en LDL-sänking till nivåer under 1.8 mmol/l. Syfte Syftet med detta arbete var att undersöka vilka behandlingseffekter som finns vid läkemedelsbehandling som sänker LDL till låga nivåer vid sekundärprevention för hjärtinfarktpatienter och om de nuvarande behandlingsriktlinjerna på nivåer under 1.8 mmol/l kan anses rimliga. Vidare gjordes en ansats för att belysa frågan om huruvida LDL-sänkning eller pleiotropa effekter kan förklara effekten vid statinbehandling. Resultat Behandling med hög dos statin som sänker LDL till låga nivåer minskar risken för större kardiovaskulära/koronara händelser. Effekten beror främst på minskat antal hjärtinfarkter och revaskulariseringsprocedurer. Effekten på koronar/kardiovaskulär mortalitet förefaller emellertid vara i bästa fall liten. Samma mönster sågs i studier av PCSK9-hämmaren evolocumab och NPC1L1-hämmaren ezetimib. Då dessa läkemedel sänker LDL genom andra mekanismer än statiner indikerar detta att LDL-sänkning i sig har en effekt men pleiotropa effekter kan inte uteslutas. Slutsats Läkemedelsbehandling som sänker LDL till nivåer under 1.8 mmol/l förefaller ha effekt och därmed är det inte orimligt att ha ett sådant behandlingsmål. Det går emellertid inte att finna en optimal nivå för LDL-koncentrationen i plasma baserat på de studier som gjorts. NNT-talen blir relativt höga och en betydande residualrisk kvarstår även vid sänkning till låga LDL-nivåer vilket indikerar potentiell vikt av tidigare insatt LDL-sänkande behandling men även ett behov av nya behandlingsformerSummary Background Despite substantial reductions in the incidence of myocardial infarction, the incidence remains high. Rupture of an atherosclerotic plaque within the coronary arteries is the most important direct causal factor. Atherosclerosis typically develops slowly and silently and can be described as a build-up of cholesterol-containing plaques within the artery wall. Theories of the causal mechanisms behind atherosclerosis point to a high degree of complexity. Most theories focus on an interaction between inflammatory processes, cholesterol-containing lipoproteins and dysfunction of the endothelial cells within the artery wall. Much focus has been put on the role of cholesterol-containing low-density lipoprotein (LDL). This lipoprotein seems to have a direct causal role in the process. Such a standpoint is based on animal experiments, observational studies, randomized clinical trials with LDL-lowering drugs and Mendelian randomization studies. Treatment guidelines for patients with myocardial infarction therefore recommend LDL-lowering therapy. These guidelines recommend treatment with a high dose statin and some include recommendations to lower LDL to levels below 1.8 mmol/l (69 mg/dl). Objective The aim of this thesis was to look at the treatment effects of lowering LDL to low levels for secondary prevention of myocardial infarction and whether the current recommendations of 1.8 mmol/l or less are reasonable. A second objective was to elucidate the question of whether statins have other, pleiotropic effects beside their LDL-lowering capacity. Searches were conducted in pubmed for randomized clinical statin-trials where low average LDL-levels were obtained. Further, a trial with PCSK9-inhibitor evolocumab and a trial with NPC1L1-inhibitor ezetimibe were included in order that the effects of these drugs could be compared with the effects of statins. Thereby, the question of statin-pleiotropy could be analyzed. Results Treating patients with a high dose statin to obtain lower levels of LDL reduced the risk of major coronary/cardiovascular events when compared with a low dose statin. The absolute risk reduction was however low. The effect was driven mainly by a reduction in the number of myocardial infarctions and coronary revascularization procedures whereas the effects on mortality seem absent or at best rather modest. The same pattern was seen in the FOURIER-trial where PSCK9-inhibitor evolocumab was compared with standard statin treatment. The active treatment group obtained an average LDL-level of 0.78 mmol/l (30 mg/dl). This pattern was also seen in the IMPROVE-IT-trial, where NPC1L1-inhibitor ezetimibe was compared with standard statin treatment. Conclusion Treatment to obtain low levels of LDL have an effect - even at levels below 1.8 mmol/l. LDL-lowering in and of itself seems to have an effect given the results from studies where patients were treated with evolocumab and ezetimibe. The number of patients that need to be treated to prevent one event is however high and a substantial number of patients remain at risk even at very low levels of LDL. This implies the need for other forms of therapy or initiation of LDL-lowering therapies at earlier stages for selected groups of patients before they experience a myocardial infarction
39
Grewe, Nicole. "Einfluß einer Virusdosiseskalation beim adenoviralen LDL-Rezeptorgentransfer im Kaninchenmodell." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2005. http://dx.doi.org/10.18452/15302.
Full textAbstract:
Die autosomal-dominant vererbte Familiäre Hypercholesterinämie ist durch eine exzessive Erhöhung der LDL-Serumcholesterinspiegel gekennzeichnet und bedingt aufgrund einer prämaturen Atherosklerose den frühzeitigen Tod der Patienten. Da ursächlich ein defekter LDL-Rezeptor (LDL-R) zugrundeliegt, der durch Mutationen im Bereich des LDL-R-Gens hervorgerufen wird, kommt der Gentherapie als potentieller Behandlungsmöglichkeit ein besonderer Stellenwert zu. Diese Arbeit untersuchte den Einfluß einer Virusdosiseskalation auf Cholesterinsenkung und Langzeitexpression im adenoviral vermittelten LDL-R-Gentransferversuch im Kaninchenmodell. Hierfür wurden 7 Watanabe Heritable Hyperlipidemic Kaninchen, welche an einer vergleichbaren kongenitalen Hypercholesterinämie durch einen LDL-R-Defekt leiden, mit unterschiedlichen Dosierungen eines Adenovirus des Serotyps 5 therapiert, der die Gensequenz für den humanen LDL-R enthielt. Vor und nach Therapie wurden Bestimmungen der Serumcholesterinkonzentrationen und LDL-Stoffwechselkinetiken mit 125I-LDL sowie semiquantitative szintigraphische Auswertungen durch 111In-LDL-Scans durchgeführt. Hierbei mußte festgestellt werden, dass die adenoviral vermittelte transgene Expression des LDL-R durch die Bestimmung des Serumcholesterins nicht korrekt wiedergegeben wird. Denn zum einen konnte bei der Bestimmung des Serumcholesterins ein dosisabhängiger Effekt beobachtet werden, dieser zeigte sich bei den Stoffwechselkinetiken mit 125I-LDL und bei den Scanuntersuchungen mit 111-In-LDL jedoch nicht. Zum anderen kam es innerhalb von 12-18 Tagen nach Gentransfer zu einem Wiedererreichen der Serumcholesterinausgangswerte, wohingegen die in vivo-Stoffwechselkinetiken eine erhöhte Abbaurate radiomarkierter LDL und die Szintigraphie eine LDL-R-Expression über die gesamte Dauer des Experimentes von 120 Tagen belegten.Familial hypercholesterolemia is an autosomal dominantly inherited disease characterized by an exzessive elevation of serum LDL cholesterol which leads to premature atherosclerosis and an early death of the patients. As the reason is a defective LDL receptor (LDLR) caused by mutations in the gene encoding LDLR, gene therapy plays an increasingly important role as a treatment possibility. This paper examined the influence of an escalation of the virus dose on the cholestorol reduction and long-term expression in the adenovirally mediated LDLR gene therapy experiment using a rabbit animal model. To facilitate this 7 Watanabe Heritable Hyperlipidemic rabbits, suffering from an equivalent congenital hypercholesterolemia due to a LDLR defect, were treated with different doses of a serotype 5 adenovirus which contained the gene sequence of the human LDLR. Pre and post gene therapy measurements of the serum cholesterol levels and kinetics of LDL metabolism with 125I-LDL were performed, as well as semiquantitative scintigraphic analysis of 111In-LDL scans. The finding was that the adenovirally mediated transgene expression of the LDLR was not correctly reflected by the measurement of the serum cholesterol levels. This was because of a dose dependant effect concerning the measurements of the serum LDL cholesterol levels, which did not appear regarding the kinetics of LDL metabolism with 125I-LDL and the scans with 111In-LDL. Moreover, the serum cholesterol levels reached their initial value within 12-18 days post gene transfer whilst the in vivo-kinetics of LDL metabolism showed an increased catabolic rate of radiolabeled LDL and the scintigraphy indicated a LDLR expression for the whole period of the experiment lasting 120 days.
40
Oliveira, Ivarsson Martin. "Verifiering av P-LDL-kolesterol på Beckman Coulter AU680." Thesis, Linnéuniversitetet, Institutionen för kemi och biomedicin (KOB), 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-85556.
Full textAbstract:
Kolesterol transporteras i blodet med hjälp av lipoproteinpartiklar. Höga nivåer av low-density lipoprotein (LDL)-kolesterol i blodet är en riskfaktor för kardiovaskulär sjukdom. Koncentrationen av LDL-kolesterol kan beräknas med hjälp av Friedewalds formel men det finns även metoder där LDL-kolesterol kan analyseras direkt. Syftet med arbetet var att verifiera metoden direkt LDL-kolesterol på analysinstrumentet Beckman Coulter AU680. Metodens inomserie- och totalimprecision analyserades. Två korrelationsstudier utfördes mellan direkt LDL-kolesterol och beräknat LDL-kolesterol, en med 43 patientprover med triglycerider < 4,5 mmol/L och en med 11 patientprover med triglycerider > 4,5 mmol/L. Friedewalds formel ska egentligen inte användas vid triglycerider > 4,5 mmol/L, men i detta fall användes formeln ändå för att utvärdera eventuella skillnader mellan metodernas resultat vid höga triglyceridkoncentrationer. Vid analys av metodens inomserieimprecision blev variationskoefficienten (CV) omkring 0,5 % vid analys av både den låga kontrollen (A1) och den höga kontrollen (A2). CV för totalimprecisionen blev 1,21 % vid analys av A1 och 1,11 % vid analys av A2. Korrelationsstudierna visade ett linjärt samband mellan metoderna men den direkta metoden gav något högre resultat vid lägre koncentrationer och något lägre resultat vid högre koncentrationer jämfört med beräknat LDL-kolesterol. Vid triglycerider > 4,5 mmol/L gav den direkta metoden betydligt högre resultat än beräknat LDL-kolesterol. Slutsatsen blev att metoden hade god precision. Överensstämmelsen mellan metodernas resultat var relativt bra för proverna med triglycerider < 4,5 mmol/L. Vid triglycerider > 4,5 mmol/L var differensen mellan metoderna stor, troligtvis på grund av falskt för låga resultat från beräknat LDL-kolesterol.Cholesterol is transported in the blood by lipoproteins. High levels of low-density lipoprotein (LDL)-cholesterol in the blood is a risk factor for cardiovascular disease. The concentration of LDL-cholesterol can be calculated using the Friedewald formula but there are also methods that measure LDL-cholesterol directly. The aim of this study was to verify the method P-LDL-cholesterol on a Beckman Coulter AU680 analyzer. Within-run imprecision and total imprecision were analyzed. The correlation between direct LDL-cholesterol and calculated LDL-cholesterol was examined using 43 patient samples with triglyceride levels < 4,5 mmol/L and 11 patient samples with triglyceride levels > 4,5 mmol/L. The Friedewald formula is not supposed to be used on triglyceride levels > 4,5 mmol/L, but in this case the formula was used anyway to evaluate differences between the methods at high triglyceride concentrations. The coefficient of variation (CV) for the within-run imprecision was about 0,5 %, both for the low control (A1) and the high control (A2). Total imprecision had a CV of 1,21 % for A1 and 1,11 % for A2. There was a linear relationship between the methods, but the direct method gave slightly higher results at low concentrations and slightly lower results at high concentrations compared to calculated LDL-cholesterol. At triglyceride levels > 4,5 mmol/L the results from the direct method was considerably higher than calculated LDL-cholesterol. The conclusion is that the precision of the method was good. The correlation between the results from direct LDL-cholesterol and calculated LDL-cholesterol was relatively high for samples with triglyceride levels < 4,5 mmol/L. At triglyceride levels > 4,5 mmol/L there was a big difference between the methods, probably because of falsely low results from calculated LDL-cholesterol.
41
Engel, Daiane Fátima. "Evidências experimentais da associação entre a hipercolesterolemia e a depressão." reponame:Repositório Institucional da UFSC, 2016. https://repositorio.ufsc.br/xmlui/handle/123456789/175889.
Full textAbstract:
Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Bioquímica, Florianópolis, 2016.Made available in DSpace on 2017-05-23T04:21:08Z (GMT). No. of bitstreams: 1 345667.pdf: 5164258 bytes, checksum: a6d6e4f807243c1d227b1ae23222193a (MD5) Previous issue date: 2016
A hipercolesterolemia familiar é uma doença do metabolismo das lipoproteínas causada principalmente por mutações no gene do receptor de lipoproteína de baixa densidade (LDL). A resultante perda da função do receptor de LDL (LDLr) tem como principal consequência o aumento das concentrações plasmáticas de colesterol. Estudos clínicos reportam, com certa frequência, a comorbidade entre a hipercolesterolemia e transtornos de humor, como a depressão. Além disso, aumento na permeabilidade da barreira hematoencefálica, redução na proliferação celular hipocampal adulta e prejuízos comportamentais de aprendizado e memória foram reportadas em camundongos LDLr-/- (nocautes para o LDLr, modelo animal de hipercolesterolemia familiar). O primeiro objetivo deste estudo foi verificar o comportamento de camundongos LDLr-/- em testes preditivos para a depressão. Sabendo que a neurogênese hipocampal adulta é importante para a manutenção do humor e da cognição, o segundo objetivo foi verificar se a comorbidade entre a hipercolesterolemia e a depressão envolve alterações na neurogênese hipocampal adulta. Nossos resultados demonstraram que os camundongos LDLr-/- apresentaram comportamento tipo-depressivo (anedonia, diminuição do auto-cuidado e da motivação) em testes preditivos para depressão. Este comportamento tipo-depressivo foi revertido pelo tratamento antidepressivo repetido (fluoxetina, 7 dias). Os camundongos LDLr-/- também apresentaram aumento na atividade da monoamina oxidase (MAO) A no córtex cerebral e no hipocampo. Neste estudo as análises comportamentais também revelaram comprometimento de função cognitiva dependente do giro denteado (GD) hipocampal, o que corroborou a redução na proliferação e neurogênese das células precursoras neuronais (CPNs) observada nesta estrutura. Em outra etapa experimental, em cultivo primário de CPNs isoladas do GD de camundongos C57BL/6 adultos, foi caracterizada uma maior expressão gênica de enzimas de síntese de colesterol e do LDLr no estágio proliferativo, enquanto os genes do LRP1 e de enzimas de degradação têm sua expressão aumentada durante a diferenciação celular. Corroborando os resultados obtidos em camundongos LDLr-/-, tanto a exposição destas células à LDL humana isolada, quanto o silenciamento gênico do LDLr (LDLr siRNA), reduziram a proliferação de CPNs. O tratamento com LDL também reduziu a diferenciação neuronal de CPNs, induziu acúmulo de gotículas lipídicas intracelulares e inibiu a expressão gênica de enzimas de síntese do colesterol e do LDLr. Por sua vez, o LDLr siRNA reduziu também os níveis de RNAm do LRP1. A análise de microarray revelou que a LDL inibiu fortemente processos celulares relacionados ao metabolismo do colesterol. O tratamento com siRNA alterou a expressão relativa de muitos genes, no entanto a análise de ontologia não revelou associação significativa destes genes com processos celulares específicos. Ainda, ambos os tratamentos aumentaram a capacidade de reserva das CPNs no teste de função mitocondrial. Em conjunto, estes resultados caracterizam o fenótipo tipo-depressivo e a redução da neurogênese hipocampal adulta em um modelo experimental de hipercolesterolemia familiar, sendo que a neurogênese parece ser influenciada tanto pela presença da LDL no nicho neurogênico quanto pela função do LDLr. Conjuntamente, estes dados destacam o papel do metabolismo do colesterol na neurogênese adulta e reforçam as observações clínicas que associam a hipercolesterolemia à depressão.
Abstract : Familial hypercholesterolemia is a lipoprotein metabolism disorder caused primarily by mutations in the low-density lipoprotein receptor (LDLr) gene, causing loss of function of the LDLr and increased plasma cholesterol. Clinical studies frequently report comorbidity between hypercholesterolemia and depression. Supporting those observations, pre-clinical studies from our group have shown impairments in the CNS of LDLr-/- mice (knockout mice for the LDLr, a murine model of familial hypercholesterolemia). Increased blood brain barrier permeability, reduced hippocampal cell proliferation, and learning and memory impairments in behavioral tasks are some of the CNS abnormalities observed in these mice. The first aim in this study was to verify the behavior of LDLr-/- mice in predictive tasks for depression. Considering that adult neurogenesis is thought to play a role in both mood regulation and cognition, the following objective in this study aimed to avaluate if an impairment in proliferation and differentiation of hippocampal adult neural stem cells (aNSC) may be underlying the co-morbidity between hypercholesterolemia and depression. Endorsing this hypothesis, in the present study we show that LDLr-/- mice present a depressive-like behavior (anhedonia, reduction in self-care and motivational behavior). This depressive-like behavior was abolished by repeated antidepressant treatment (fluoxetine, 7 days). In addition, the LDLr-/- mice presented increased MAO-A activity in the cerebral cortex and hippocampus. Moreover, a deficit in dentate gyrus (DG)-dependent cognitive task was observed in these mice using a DG-dependent behavioral test, corroborating the reduction in DG cell proliferation and neurogenesis. Primary culture of aNSCs isolated from the DG of adult C57BL/6 mice demonstrated that the expression of enzymes involved in cholesterol synthesis (HMG-CoA reductase and squalene synthase) and of LDLr peaks during the proliferation stage of the neurogenic process. On the other hand, the expression of LRP1, cholesterol 24-hydroxylase, and sterol 27-hydroxylase is up-regulated during the differentiation stage. In agreement with the observations from the LDLr-/- mice, exposure to both human LDL as well as silencing of the LDLr (using an LDLr siRNA) reduced cell proliferation and/or neuronal differentiation of aNSCs monolayers. LDL treatment was also associated with an increase in the number of lipid droplets and a down-regulation of mRNA levels of the LDLr and enzymes involved in cholesterol synthesis, whereas LDLr siRNA also reduced LRP1 gene expression. Microarray analysis showed that LDL down-regulated cholesterol metabolism. On the other hand, LDLr siRNA altered the relative expression of hundreds of genes, however a gene ontology analysis failed to define a clear relationship with cellular functions. In addition, both treatments increased the reserve capacity of aNSCs to respond to mitochondrial stress. Altogether, this study describes the depressive-like phenotype and deficits in adult hippocampal neurogenesis in an experimental model of familial hypercholesterolemia. These deficits may result from LDL being present in the neurogenic niche and from compromised LDLr function. In conclusion, the present data implicate cholesterol metabolism as a modulator of adult hippocampal neurogenesis and support the observed co-morbidity between hypercholesterolemia and depression.
42
Chouinard, Julie. "Effets des LDL natives et oxydées sur l'évolution des propriétés biomécaniques des cellules endothéliales et imagerie des LDL par microscope à force atomique." Mémoire, Université de Sherbrooke, 2007. http://savoirs.usherbrooke.ca/handle/11143/1351.
Full textAbstract:
Cette étude vise à définir l'effet des lipoprotéines de basses densité natives (LDL) et oxydées (ox-LDL) sur les fonctions des cellules endothéliales en relation avec les processus physiopathologiques de l'athérosclérose. Le microscope à force atomique (AFM) fut utilisé en combinaison avec les méthodes biochimiques traditionnelles afin d'acquérir de l'information sur les propriétés biomécaniques des cellules endothéliales. L'AFM est un outil permettant l'acquisition d'images et de mesures de forces quantitatives concernant les propriétés viscoélastiques des cellules vivantes selon leur exposition aux LDL ou ox-LDL. L'AFM rassemble localement des informations sur la membrane cellulaire et le cytosquelette des cellules et ce, de manière non invasive. Il est ensuite possible de corréler les résultats obtenus avec les marquages immunohistochimiques afin d'évaluer la réponse cellulaire suite à une exposition à des LDL ou ox-LDL. Ces données recueillies, les protocoles étant au point, il ne restera plus qu'à effectuer les tests avec les antioxydants afin de déterminer les agents et les dosages appropriés permettant une protection salutaire de l'endothélium. Ce travail amène donc de nouvelles connaissances sur les mécanismes moléculaires fondamentaux de la dysfonction endothéliale en vue éventuellement de développer de nouvelles thérapies cytoprotectrices efficaces. Une méthode d'imagerie des LDL a également été mise au point en utilisant l'AFM. Il est maintenant possible d'obtenir des images de bonne qualité permettant aussi de mesurer les dimensions de LDL individuelles. Cette technique pourrait entre autre servir à évaluer des pathologies touchant les LDL comme le diabète.
43
Chouinard, Julie. "Effets des LDL natives et oxydées sur l'évolution des propriétés biomécaniques des cellules endothéliales et imagerie des LDL par microscope à force atomique." [S.l. : s.n.], 2007.
Find full text
44
Neels, Jacobus Gerardus. "LDL receptor-related protein molecular analysis and identification of new ligands /." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2001. http://dare.uva.nl/document/60201.
Full text
45
Gandjini, Hassan. "Immunoréactivité de l'apolipoprotéine B humaine : variations expérimentales et physio-pathologiques." Dijon, 1991. http://www.theses.fr/1991DIJOS034.
Full textAbstract:
L'étude de l'immunoréactivité des lipoprotéines de faible densite (LDL) a été entreprise à l'aide d'anticorps monoclonaux dirigés contre différentes parties de l'apolipoprotéine B (apo B). Le fractionnement des LDL humaines par ultracentrifugation zonale et par chromatographie de filtration sur gel a montré l'existence de sous-populations de particules de taille et de composition chimique différentes. Les sous-populations de grande taille, plus riches en lipides, sont mieux reconnues par les anticorps monoclonaux anti-apo B. L'accessibilité vis-a-vis des anticorps monoclonaux diminue dans les LDL de petite taille avec la diminution du rapport lipide/protéine. La relation entre accessibilité des épitopes et la composition lipidique a été vérifiée dans les LDL oxydées. L'incubation des LDL in vitro en présence des ions Cu++ ou de l'association phospholipase A2+lipoxygenase, est suivie d'une diminution importante de leur teneur en acides gras polyinsaturés ainsi qu'en esters de cholestérol. Ce changement important de la composition lipidique lors de l'oxydation des LDL est suivi par une diminution de l'immunoréactivité des épitopes les plus en contact des lipides. A l'inverse l'immunoréactivité d'un épitope situé au niveau de la partie N-terminale dans une partie de l'apo B qui est moins au contact de lipides est peu altérée. La sensibilité d'un épitope à l'oxydation dépendrait donc de sa localisation et de son environnement lipidique. Le modèle de LDL-aphérèse a été choisi pour approcher les changements d'immunoréactivité des LDL in vivo. Il a été montré que la composition et l'immunoréactivité des LDL à la suite du traitement aphérétique étaient différents des lLDLavant le traitement. Les particules après LDL-aphérèse pourraient être les LDL nouvellement synthétisées différentes de celles ayant subi des modifications structurales par sejour prolongé dans l'espace intravasculaire. Les résultats de ce travail ont montré que les modifications de la composition lipidique des LDL entrainent des changements au niveau de l'accessibilité des épitopes vis-a-vis des anticorps monoclonaux. Les anticorps monoclonaux pourraient constituer un moyen d'étudier les changements de la conformation de l'apo B aussi bien in vitro qu'in vivo.
46
Bourbiaux, Kévin. "Développement de peptides structurés pour l’inhibition de l’interaction PCSK9/LDLR et le rétablissement de l’absorption cellulaire du LDL-c." Thesis, Montpellier, 2020. http://www.theses.fr/2020MONTS009.
Full textAbstract:
La proprotéine convertase subtilisine/kexine de type 9 (PCSK9) régule la concentration des récepteurs des lipoprotéines de basse densité (LDLR) au niveau de la membrane cellulaire et par conséquent le taux de LDL-cholestérol dans le système vasculaire. PCSK9 est donc une cible essentielle dans le traitement des maladies cardiovasculaires (MCV). A ce jour, les anticorps monoclonaux anti-PCSK9 associés aux statines est la seule thérapie disponible ciblant PCSK9 en dépit des risques d’immunogénicité, une administration sous-cutanée contraignante et un coût élevé. Néanmoins, de petits peptides possédant des structures tridimensionnelles très stables se sont avérés être des inhibiteurs prometteurs de l’interaction entre PCSK9 et le LDLR induisant une augmentation significative de l’absorption du LDL dans les cellules. A partir de ces séquences, nous avons synthétisé des peptides stabilisés par des agrafes, avec un patch poly-lysine (technologie SIP) à l’extrémité C-terminale mais également des séquences chimériques afin de développer des analogues très actifs et résistants à la protéolyse. Nous avons obtenu des composés mille fois plus affins pour PCSK9 que le peptide de référence Pep2-8, capables de rétablir l’absorption du LDL dans les cellules pour de très faibles concentrations (IC50 = 175 nM). Les structures tridimensionnelles des composés clés ont été étudiées par dichroïsme circulaire (CD) et résonance magnétique nucléaire (RMN) afin d’étudier leurs relations structure-activitéProprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as a regulator of low density lipoprotein receptor (LDLR) on the cell membrane and therefore plays a major role in cardiovascular diseases (CVD). To date, only monoclonal antibodies (mAbs) to PCSK9 are used associated with statins in therapies, despite a potential immunogenicity, a restrictive mode of administration and a high cost. Beside, small peptides with discrete three-dimensional structures were found to inhibit the interaction between PCSK9 and the LDLR, increasing the LDL-uptake. Starting from these sequences, we used various strategies incorporating staples and/or C-terminal lysine patches (SIP technology), synthesizing chimeric sequences to develop highly potent compounds resistant to enzymatic degradation. We obtained derivatives that have a 1000-fold stronger affinity than the parent peptide with high biological activities (IC50 = 175 nM). The three-dimensional structures of key compounds were extensively studied by circular dichroim (CD) and nuclear magnetic resonance (NMR) to investigate their structure-activity relationship
47
Soares, Evelise Aline 1978. "Efeitos da hiperlipidemia e sinvastatina sobre a morfologia, resistência mecânica e capacidade osteogênica em camundongos knockout do gene do receptor de LDL (LDLr-/-)." [s.n.], 2011. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317641.
Full textAbstract:
Orientador: José Angelo CamilliTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
Made available in DSpace on 2018-08-19T19:59:03Z (GMT). No. of bitstreams: 1 Soares_EveliseAline_D.pdf: 3197082 bytes, checksum: ca95784093e801f419ec02ca8aea5020 (MD5) Previous issue date: 2011
Resumo: Introdução: O tecido ósseo pode sofrer alterações em suas propriedades bioquímicas, morfológicas, bioquímicas e biomecânicas sob a influência de determinadas doenças. Níveis elevados de colesterol e hiperlipidemia podem causar alterações no osso, comprometendo a osteogênese e resistência mecânica. A sinvastatina é um medicamento do grupo de estatinas mais comumente utilizado para o tratamento d hiperlipidemia, reduzindo o nível de colesterol. Além disso, estudos com estatinas têm demonstrado bons resultados na prevenção e tratamento da osteoporose. Objetivos: Avaliar o efeito da hiperlipidemia e da utilização de sinvastatina sobre as propriedades biomecânicas, a estrutura do osso cortical e trabecular e osteogênese em camundongos LDLr(-/-) e selvagens. Métodos: Neste estudo foram utilizados camundongos do tipo selvagem (C57BL6) (Grupo W) e camundongos homozigotos para a ausência do gene receptor LDL (LDLr-/-) (Grupo L), todos do sexo masculino com 3 meses de idade. Os animais foram divididos em dois grupos experimentais, que foram subdivididos em quatro grupos de 12 animais cada: Experimento I (grupo W - ração padrão; Grupo WH - dieta hiperlipídica; Grupo L - ração padrão e Grupo LH - dieta hiperlipídica) e Experimento II tratados com sinvastatina (S) (Grupo WS - ração padrão; Grupo WHS - dieta hiperlipídica; Grupo LS - ração padrão e Grupo LHS - dieta hiperlipídica). Após 15 dias de experimentação um defeito ósseo de 3mm de diâmetro foi produzida cirurgicamente no osso parietal direito em cada animal. No final de 60 dias de experimentação os animais foram sacrificados. O sangue foi coletado e os fêmures e o osso parietal direito foram retirados para estudo histológico e mecânico. Resultados: Os dados obtidos neste estudo originou três artigos. O primeiro artigo "Efeitos da hiperlipidemia sobre as propriedades biomecânicas e morfológicas do fêmur de camundongos LDLr(-/-)" aceito para publicação no Journal of Bone and Mineral Metabolism, o segundo "Efeitos da sinvastatina sobre as propriedades morfométricas e mecânicas no fêmur de camundongos" formatado para submissão ao Journal of Orthopaedic Research e o terceiro artigo "Efeitos da hiperlipidemia e sinvastatina na reparação óssea de defeitos na calvária de camundongos LDLr-/-" esta sendo preparado para a publicação. Conclusão: A dieta hiperlipídica causa alterações na integridade óssea e que o uso da sinvastatina foi eficaz para preservar as propriedades biomecânicas do fêmur nos animais tratados com dieta comercial, no entanto, seu efeito sobre o tecido ósseo pode ser comprometido pela ingestão de uma dieta rica em gorduras. A osteogênese foi restrita nos camundongos LDLr-/-, principalmente nos grupos alimentados com dieta rica em gorduras
Abstract: Introduction: The bone tissue can suffer alterations in their biochemical morphological and biomechanical properties under influence of certain diseases. High levels of cholesterol and hyperlipidemia can cause changes in the bone, compromising osteogenesis and mechanical strength. The simvastatin is a drug of the statins group most commonly used for the treatment of hyperlipidemia, reducing the cholesterol level. Additionally, studies with statins have demonstrated good result in the prevention and treatment of osteoporosis. Objectives: Evaluate the effect of hyperlipidemia and the use of simvastatin on the biomechanical properties, structure of cortical and trabecular bone and osteogeneses in LDLr(-/-) and wild-type mice. Methods: In this study were used wild-type (W) mice (C57BL6) and homozygous mice for the absence of the LDL receptor gene LDLr-/- (L), all male with 3 months of age. The animals were divided into two experimental groups that were subdivided into four groups of 12 animals each: Experiment I (Group W - standard ration; Group WH - high-fat diet; Group L - standard ration; Group LH - high-fat diet) and Experiment II with simvastatin (S) (Group WS - standard ration; Group WHS - high-fat diet; Group LS - standard ration; Group LHS - high-fat diet). After 15 days of experimentation a bone defect measuring 3mm in diameter was surgically produced in the right parietal bone in each animal. At the end of 60 days of experimentation the animals were euthanatized. Blood was collected and the femurs and the right parietal bone were removed for mechanical and histological study. Results: The data obtained in this study originated three articles. The first article "Effect of hyperlipidemia on femoral biomechanics and morphology in LDLr-/- mice" was accepted for publication in the Journal of Bone and Mineral Metabolism, the second "Effects of simvastatin on morphometric and mechanical properties in the femur of mice" was submitted to Journal of Orthopaedic Research and the third article "Effect of hyperlipidemia and simvastatin on bone repair of the calvaria of the LDLr-/- mice" is being prepared for publication. Conclusions: The high-fat diet caused alteration in bone integrity and the treatment with simvastatin was effective in preserving the biomechanical properties and structure of the femur in the animals treated with low-fat diet, however, its effect on bone tissue can be compromised by a high-fat diet. Osteogenesis was reduced in LDLr-/- mice, especially in the high-fat diet groups
Doutorado
Anatomia
Doutor em Biologia Celular e Estrutural
48
da, Silva Andrade Pereira Adriana. "Análise ultraestrutural da interação da lipoproteína de baixa densidade (LDL) humana com o tegumento do Schistosoma mansoni e identificação da proteína ligante de LDL." Universidade Federal de Pernambuco, 2008. https://repositorio.ufpe.br/handle/123456789/1268.
Full textAbstract:
Made available in DSpace on 2014-06-12T15:48:27Z (GMT). No. of bitstreams: 2
arquivo1276_1.pdf: 1492422 bytes, checksum: a909298503f5ea7da3bf64aee390832f (MD5)
license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5)
Previous issue date: 2008Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
A esquistossomose mansônica é uma doença endêmica em várias partes das América e da África, causada pelo Schistosoma mansoni. Segundo dados da Organização Mundial de Saúde existem entre 200 e 300 milhões de pessoas infectadas no mundo e aproximadamente 1 bilhão sob risco. O verme adulto do Schistosoma mansoni adquiriu uma habilidade peculiar para escapar do ataque do sistema imune do hospedeiro. Muitos mecanismos têm sido propostos para explicar a sobrevivência do parasita, um deles é a aquisição de lipoproteínas plasmáticas. O que chama a atenção para as lipoproteínas nestes mecanismos é o fato de os esquistossômulos não sintetizarem nem colesterol, nem ácidos graxos de cadeia longa, entretanto, estes compostos estão presentes nas suas estruturas. Provavelmente, eles adquirem do hospedeiro através da interação do tegumento do verme com as lipoproteínas no sangue do animal infectado. Neste trabalho, microscopia eletrônica de varredura, eletroforese 2-D e immunoblotting foram utilizadas como ferramentas para estudar a interação da lipoproteína de baixa densidade (LDL) com o tegumento do Schistosoma mansoni e identificar a proteína ligante de LDL. Depois de 50 dias de infecção (100 cercárias, cepa São Lourenço da Mata - SLM), camundongos albinos (Mus musculus) foram sacrificados e os vermes adultos retirados, os quais foram separados para incubação com LDL para a microscopia eletrônica de varredura e preparação do extrato para identificação da proteína ligante de LDL. Os vermes foram lavados e incubados em meio de cultura RPMI 1640 + 10% (v/v) de soro deficiente de lipoproteína (LPDS), contendo 40 μg de LDL/mL durante 30, 60, 120 min. Vermes controles foram processados da mesma forma sem LDL. O extrato de proteínas foi obtido e 200 μg de proteínas foram aplicadas em fitas gradiente de pH imobilizado (IPG strip), 7 cm, pH=3-10, seguidos de focalização isoelétrica no sistema Multiphor II (GE Healthcare) e SDS-PAGE. Proteínas foram transferidas para membranas de PDVF, e bloqueadas com caseína 3%. Subsequentemente, incubações foram feitas com soro humano, anticorpo policlonal anti-LDL (chicken) e conjugado peroxidase anti-chicken (IgG). A membrana foi revelada com substrato TMB e duas bandas foram identificadas apresentando pesos moleculares e pontos isoelétricos (pI) de 55.5 kDa e pI 5.12 e de 28.5 kDa e pI 7.17, respectivamente. Os resultados da microscopia eletrônica de varredura demonstraram uma maior interação de partículas de LDL com a região dorsal mediana do parasita, em relação à outras regiões do tegumento. Agregados lipoprotéicos foram observados nas incubações de 30 e 60 min, sendo verificado uma diminuição na incubação de 120 min. O tamanho das partículas de LDL diminuiu com o tempo de incubação, esses resultados sugerem que a redução do tamanho das partículas pode ser devido ao uso dos lipídeos das lipoproteínas pelo verme. Concluímos que a identificação da proteína ligante poderá ajudar novos projetos terapêuticos, levando a um bloqueio da interação LDL/parasita e consequentemente a morte dos vermes
49
Oliveira, Antonio Altair Magalhães de. "Cinética plasmática de uma emulsão lipídica que se liga aos receptores da lipoproteína de baixa densidade - em pacientes com doença arterial coronariana." Universidade de São Paulo, 2000. http://www.teses.usp.br/teses/disponiveis/9/9132/tde-27062008-161729/.
Full textAbstract:
A cinética plasmática de uma emulsão lipídica, que se liga aos receptores de LDL, foi estudada em 23 pacientes com Doença Arterial Coronariana (DAC) e em 16 indivíduos sadios (não apresentaram lesões obstrutivas, nem irregularidades, após serem submetidos à cineangiocoronariografia). Foram selecionados 39 participantes, sendo 30 do sexo masculino e 9 do sexo feminino, na faixa etária de 30 a 84 anos, com índice de Massa Corpórea (IMC) entre 21 e 41 ( kg/m2 ) , divididos em 2 grupos: DAC e Sadio. Após jejum de 12 horas, foram coletadas amostras de sangue total para determinação dos níveis séricos de lipídios e apolipoproteínas. A seguir foram injetadas, endovenosamente, emulsões com marcação radioativa, constituídas por lípides puros (40 mg), trioleína (TG) 1 mg, oleato de colesterol (CE) 20 mg, colesterol (CL) 0,5 mg e os isótopos radioativos 14C-oleato de colesterol e 3H-colesterol. 3H-colesterol. A cada participante foi administrado um volume da emulsão, correspondente à atividade de 37 kBq para o isótopo 14C e de 74 kBq para o isótopo 3H. Amostras de sangue foram colhidas nos intervalos 0,08 , 1, 4, 10 e 24 h , após a aplicação da emulsão. O colesterol-éster e o colesterol livre foram isolados e tiveram suas radioatividades medidas em cintilador. As taxas fracionais de remoção do 14C-oleato de colesterol e do 3H-colesterol livre, foram estimadas por análise compartimental, com auxílio de um programa computacional. Observou-se que: - não há diferença entre os dois grupos, em relação à idade, porcentagem de indivíduos do sexo masculino e feminino e o IMC. Pacientes do grupo DAC apresentam níveis de HDL-colesterol (p=0,0005) e de apolipoproteína A 1 ( p=0,009), reduzidos em relação aos indivíduos do grupo Sadio. As taxas fracionais de remoção do 14C-oleato de colesterol não diferiram entre os grupos DAC e Sadio (0,107± 0,026 horas -1VS 0,064± 0,009 horas -1, p=ns ). A taxa fracional de remoção do 3H-colesterol livre foi maior no grupo DAC do que no Sadio (0,152±0,014 horas -10,096± 0,019 horas-1, p=0,032). A taxa fracional de remoção do 3H-colesterol livre correlacionou-se diretamente com os níveis plasmáticos de triglicérides (r=0,37, p=0,002) e inversamente com os de HDL-C(r=-0,47, p=0,002) e LDL-C (r= -0,35, p = -0,03). Não houve diferença significativas entre os perfis lipídicos e de apolipoproteínas dos pacientes do grupo DAC e os dos indivíduos do grupo SadioThe plasma kinetics of a lipidic emulsion that binds to LDL receptors was studied in patients with coronary artery disease (CAD) and in control subjects without CAD as documented by coronary angiography. CAD group consistent in 23 subjects (20 male and 3 of female sex , 37-70 year 21-37 body mass index), whereas the healthy control group had 16 subjects (10 male,30-84 aged, 21-41 body mass index). The emulsion was prepared by ultrassonic irradiation of a lipid mixture in aqueous buffer and purified by a two-step ultracentrifugation procedure. The emulsion composition was lipids (40 mg), triglycerides (1 mg), cholestero! (0,5 mg), cholesterol oleate( 20 mg) and was labeled with C14 and 3H . The emulsion vvas injected intravenously into the subjects after a 12 h fast and plasma samples were colected at 0.08, 1, 4, 10 and 24 hour time periods after the injection for determination of the plasma decaying curves of the radioactive lipids. \\/\\lith this purpose, the plasma samp!es were lipid extracted and the lipids were separated by thin-Iayer chromatography. Radioactivity was counted in a liquid scintillation solution. The plasma Fractional Clearance Rate (FC R, in h -1 ) was estimated from the decaying curves by the method of minimum squares, with the aid of a computational software. The two study groups did not differ regarding age, sex, and BMI. The CAD group had smaller plasma HDL cholesterol and apolipoprotein (apo) A1 values, but LDL and VLDL cholesterol as well as apo B, were similar between the two groups. 14C-cholesteryl ester FCR-of the CAD group was not different from the controls (CAD: and Healthy:,p). However, 3H-cholesteroi FCR was greater in the CAD group than in the controls (0,152 ±0,014 h -1 vs 0,096± 0,019 h -1 ,p=0,032 ). 3H cholesterol FCR was positively correlated with triglyceride plasma concentration ( r=0,37, p=0,002) and negatively correlated with HDL (r= -0,47, p=0,002) and LDL (r= -0,35, p=0,03). Therefore, the emulsion particles were similarly removed from the circulation in both CAD and healthy groups. Disturbances of cholesterol esterification and removaI from the plasma of free-cholesterol are related with presence od CAD.
50
Gavigan, S. J. P. "Effects of fatty acids upon LDL catabolism in cultured cells." Thesis, Imperial College London, 1986. http://hdl.handle.net/10044/1/38009.
Full text