Evidence suggests that there is an immunological response of the recipient to xenograft bioprosthetic heart valves. Information on the impact of HMG-CoA reductase inhibitors (statins) and their anti-inflammatory properties on bioprosthetic valve failure remains limited. We sought to examine the efficacy of statin therapy in a rodent model of bioprosthetic valve implantation. To mimic the human scenario, fresh or glutaraldehyde-fixed aortic valve root conduits from Lewis rats or Hartley guinea pigs were microsurgically implanted intravascularly into the infra-renal aorta of Lewis rats. The syngeneic control group consisted of a fresh rat valve conduit implanted into a rat. The xenogeneic control group consisted of a glutaraldehyde-fixed guinea pig valve conduit implanted into a rat. Treatment groups consisted of xenogeneic groups treated with either daily steroids or statins. Overall, steroid treatment attenuated the inflammatory response observed within the xenogeneic glutaraldehyde-fixed valve conduits. Treatment with statins did not decrease this inflammatory response.

Cholesterol is an essential component of the cell, but excessive blood levels are a major risk factor for the development of atherosclerotic plaques that can lead to heart disease and stroke, the foremost cause of premature death in Western societies. Policosanol, a mixture of very long chain alcohols derived from sugarcane, has gained considerable attention among the public as safe and effective means to reduce blood cholesterol levels, a belief based on some early clinical studies. My research investigates one possible mechanism by which policosanol might decrease blood cholesterol levels: the inhibition of cholesterol synthesis in the liver. Previous studies with cultured hepatoma cells have indicated that policosanol suppresses HMG-CoA reductase activity, the regulatory step in cholesterol synthesis, by activation of AMP-kinase, which then inactivates HMG-CoA reductase by phosphorylation. My studies have confirmed this activation of AMP-kinase both in hepatoma cells and in whole animals after intragastric administration of policosanol. The present studies were also undertaken to identify the upstream signaling mechanism by which policosanol activates AMP-kinase. Treatment of rat hepatoma cells with policosanol increased the amount of phosphorylated CaMKK, which can directly activate AMP-kinase, but had only a small effect on LKB1, the principal activator of AMP-kinase. Intragastric administration to mice similarly activated CaMKK, but not LKB1, in the liver. To determine if metabolism of policosanol was necessary for activation of AMP-kinase, siRNA-mediated suppression of fatty aldehyde dehydrogenase, fatty acyl CoA synthase-4, or β-ketothiolase in hepatoma cells prevented the phosphorylation of AMP-kinase and HMG-CoA reductase by policosanol, indicating that metabolism of these very long chain alcohols to fatty acids and subsequent peroxisomal β-oxidation is necessary for the suppression of cholesterol synthesis. As the principal product of fatty acid -oxidation is acetyl-CoA, further studies demonstrated that addition of acetate to cells similarly activated AMP-kinase and inactivated HMG-CoA reductase. This finding argues that the activation of AMP-kinase by policosanol results from the generation of excess acetyl-CoA via peroxisomal metabolism. Finally, although the intestine is a significant source of circulating cholesterol, policosanol was unable to activate AMP-kinase in the small intestine. These findings open new perspectives for the control of cholesterol synthesis by activators of AMP-kinase.

Evidence suggests that there is an immunological response of the recipient to xenograft bioprosthetic heart valves. Information on the impact of HMG-CoA reductase inhibitors (statins) and their anti-inflammatory properties on bioprosthetic valve failure remains limited. We sought to examine the efficacy of statin therapy in a rodent model of bioprosthetic valve implantation. To mimic the human scenario, fresh or glutaraldehyde-fixed aortic valve root conduits from Lewis rats or Hartley guinea pigs were microsurgically implanted intravascularly into the infra-renal aorta of Lewis rats. The syngeneic control group consisted of a fresh rat valve conduit implanted into a rat. The xenogeneic control group consisted of a glutaraldehyde-fixed guinea pig valve conduit implanted into a rat. Treatment groups consisted of xenogeneic groups treated with either daily steroids or statins. Overall, steroid treatment attenuated the inflammatory response observed within the xenogeneic glutaraldehyde-fixed valve conduits. Treatment with statins did not decrease this inflammatory response.

In this study, we examined the effects of thyroid hormone on regulatory processes of cholesterol metabolism. Specifically, the pathways of cholesterol synthesis and cholesterol efflux were investigated. Hepatic HMG-CoA reductase (HMGR) is the rate-limiting enzyme in cholesterol synthesis. Hypothyroid rats exhibit decreased expression of this gene, which can be induced by subsequent treatment with thyroid hormone. The mechanism of this activation was previously unknown. Utilizing in vivo electroporation, we identified HMGR promoter elements necessary for the induction of HMGR by thyroid hormone. The -316/-321 element, the sterol response element, and nuclear factor-y site were all found to be necessary to induce HMGR promoter activity by thyroid hormone. We used electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) studies to demonstrate increased binding of upstream transcription factor-2 (USF-2) to the -316/-321 element in the HMGR promoter in response to thyroid hormone. Finally, co-electroporation of the wild-type HMGR plasmid with siRNA to USF-2, SREBP-2, or NF-Y nearly abolished the T3 induction as measured by promoter activity. Microarray and real-time PCR analysis demonstrated an induction of the apolipoproteins ApoA-I and ApoA-IV mRNA by T3. Serum levels of ApoA-I and ApoA-IV proteins were induced by T3. We collected serum from rats treated with or without T3 and used these sera in an in vitro macrophage efflux model. We found that T3 promoted cholesterol efflux via the ABCA1 cholesterol transporter and not via the ABCG1 transporter. We propose that the induction of serum ApoA-I and ApoA-IV by thyroid hormone promotes cholesterol efflux via the ABCA1 cholesterol transporter. Hepatic ABCG5 and ABCG8 are cholesterol transporters that promote biliary secretion of cholesterol. We utilized EMSAs to scan the shared ABCG5/G8 rat promoter for a thyroid hormone response element (TRE). We identified a TRß binding site at -392/-376 of the ABCG8 promoter. Collectively, these observations provide new insight into the cholesterol-lowering function of thyroid hormone.

Background: In the United States, 30-60% of older adults fall each year; 10-20% of these falls result in injury, hospitalization, or even death. Better prevention of falls in this population may be facilitated by broader identification of risk factors. The use of statins has emerged as a potential risk factor, but the data provide conflicted results. Purpose: To examine the relationship between statin use and falls among community-dwelling older adults. Methods: We evaluated the patient registry of a Level 1 trauma center. All patients aged > 50 years who were admitted for falls in 2015 were included (n=615). Many of these patients had been previously admitted for falls and many were later readmitted for falls. We analyzed predictors of both prior admission and readmission with linear regressions. Independent variables were self-reported balance problems, diagnosis of dementia, and the use of statins. Results: On average, patients admitted for falls were 79.9 + 9.3 years old and 28% (n=173) were taking statins. Our collection of predictors explained 14.2% of the variance in the number of prior admissions (p<0.001). In this model, the use of statins significantly predicted the number of previous fall-related admissions (95% CI: 0.07–0.50, p=0.010). This same model maintained its significance when predicting admissions for future falls (p<0.001) and the use of statins continued to predict a greater number of readmissions (95% CI: 0.04–0.36, p=0.015). Conclusion: More than 25% of all Americans age > 40 years are taking cholesterol-lowering medication; 93% of those medications are statins. Although evidence is conflicted, these data support the finding that statin therapy increases the risk of falls in older adults. Incorporating exercise training as a prophylactic measure: enhancing lipid profiles and decreasing the need for statins while also improving balance, coordination, and mobility, may reduce fall-related injuries.

The objectives of this two part prospective study were to evaluate the effects of statins on C-reactive protein (CRP), butyrylcholinesterase (BChE), lipids, and the relationships between these parameters. Subjects enrolled in this study were separated into two cohorts. The first group (study 1) consisted of 37 subjects converted from pravastatin to cerivastatin. The second group (study 2) consisted of 11 subjects with diabetes initiated on cerivastatin therapy. The subjects were followed for 12-weeks in the Lipid Clinic at David Grant Medical Center at Travis Air Force Base. CRP, BChE, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) were measured at baseline, 6-weeks, and 12-weeks. In study 1, CRP (p = 0.704) and BChE (p = 0.746) remained relatively stable over 12-weeks. The lipid panel changed significantly with TC (p < 0.001) and LDL (p < 0.001) decreasing and HDL (p = 0.017) increasing. Although TG declined numerically, it was not statistically significant (p = 0.649). A significant negative correlation was detected at baseline (r = −0.353, p = 0.032), but lost at 6-weeks and 12-weeks. In study 2, CRP declined by 42.9%, but was not statistically significant (p = 0.178). BChE remained relatively stable over 12-weeks (p = 0.666). TC (p < 0.001) and LDL (p < 0.001) declined and TG (p = 0.035) fluctuated over the course of the study. HDL increased, but it was not statistically significant (p = 0.396). Significant positive correlations were seen between CRP and TG (r = 0.908, p < 0.001) and BChE and TC (r = 0.721, P = 0.012) at baseline and BChE and TG (r = 0.64, p = 0.034) at 12-weeks. These results suggest that statin effects on CRP are independent of the lipid-lowering effects and switching statins may not affect CRP disposition. Cerivastatin does not appear to have effects on BChE activity. Lastly, a possible competitive relationship may exist between CRP and BChE. This is suggested by the negative correlation seen in study 1 and with the gain in correlation between BChE and TG as the correlation was lost between CRP and TG in study 2.

No description available.

Statins, common cholesterol control drugs, are appreciated to have promising anticancer activity through inhibition of the mevalonate pathway. Several lines of evidence suggest that certain tumours are susceptible to statins, but the underlying molecular features arbitrating this sensitivity remain unknown. We hypothesize that (i) not all statins will behave equivalently in the context of anticancer therapy, and (ii) a molecularly-defined subset of tumours are intrinsically sensitive to statins. My objectives have therefore been to further our understanding of functional differences between statins influencing their anticancer effects, and to investigate molecular features associated with statin sensitivity in breast cancer. Specifically, this thesis addresses two aims: (i) to characterize differential interactions between four statins and the xenobiotic transporter P-glycoprotein (P-gp; also known as ABCB1), and (ii) to identify molecular features associated with fluvastatin and lovastatin sensitivity in breast tumour cell lines. We first characterized the interactions of statins with P-gp in vitro and in multidrug-resistant (MDR) tumour cells. While lovastatin could directly bind to P-gp and modulate MDR, no significant interactions were observed with fluvastatin. Fluvastatin may therefore be appropriate for use in unselected patients, to avoid adverse drug interactions with coadministered P-gp substrate chemotherapeutics. Fluvastatin has also shown promise in breast cancer treatment, where molecular features predictive of statin sensitivity would be particularly valuable. A panel of 19 immortalized breast cell lines was therefore characterized for sensitivity to fluvastatin and lovastatin. Relatively statin-sensitive cells underwent apoptosis upon statin treatment, and were more likely to have an estrogen receptor alpha (ERα)-negative, basal-like phenotype. By mining available baseline gene expression data, a candidate 10-gene signature predictive of fluvastatin sensitivity was also generated. Taken together, this research provides insight into molecular markers of statin sensitivity that may facilitate fast-tracking of these drugs to clinical trials in subsets of cancer patients most likely to respond.

Introdução: Atualmente as Doenças Crônicas não Transmissíveis (DCNTs) são um dos maiores problemas de saúde pública da sociedade. É bastante claro o papel da dieta no controle do colesterol e na incidência de doenças cardiovasculares. Neste sentido, o amaranto desperta grande interesse devido a sua propriedade hipocolesterolemizante. Estudos sugerem que seu efeito hipocolesterolemizante está associado à inibição da enzima HMG-CoA redutase, chave na síntese do colesterol endógeno. Objetivo: Avaliar a atividade enzimática hepática da HMG-CoA redutase de hamsters alimentados com proteína de amaranto. Metodologia: Trinta hamsters foram divididos em 5 grupos e receberam dieta diferenciadas pela fonte protéica. Os grupos I e Icol receberam dieta com 20% de proteína de amaranto e os grupos caseína C e Ccol receberam dieta com 20% de caseína. Os grupos \"col\" apresentavam dieta com 0,1% de colesterol e 13,5% de gordura de coco. O metabolismo lipídico foi acompanhado através do monitoramento das concentrações plasmáticas de colesterol total, triacilgliceróis, HDL, e fração não-HDL nos animais. A excreção de colesterol e ácidos biliares foram quantificados nas fezes dos animais e o grau de esteatose hepática foi determinada através de análises histológicas do lobo direito do fígado. A atividade da enzima HMGR nos fígados foi medida por meio do Kit CS 1090 da Sigma-Aldrich com adaptações segundo Cong et al, 2012. A análise é baseada em espectrometria com absorbância de 340nm a 37ºC, que representa a oxidação de NADPH pela HMG-CoA redutase, na presença do substrato HMG-CoA. Conclusões: A proteína de amaranto pode ser considerado um aliado na redução dos agravos gerados pela dislipidemia, uma vez que reduziu significativamente os níveis de colesterol plasmático e gordura hepática, além de ser demonstrado seu efeito na redução da atividade da enzima HMG-CoA redutase dos animais hipercolesterolemizados que se alimentaram com proteína de amaranto. Uma vez verificado o efeito hipocolesterolemizante e seu possível mecanismo de ação por meio da enzima HMG-CoA redutase, espera-se com isso, estimular o consumo pela população brasileira produção de amaranto no Brasil, como alternativa para diversificar a dieta e a agricultura. / Introduction: Nowadays, Non-Communicable Chronic Diseases (NCCD) are a major challenge in health public. It is evident the role of diet in the control of cholesterol and incidence of cardiovascular disease. In this sense, amaranth arouses great interest due to its hypocholesterolemic property. Studies suggest that amaranth\'s hypocholesterolemic effect is associated with the inhibition of the enzyme HMG-CoA reductase, known as the key process to the endogenous cholesterol synthesis. Objective: Evaluate the hepatic enzymatic activity of HMG-CoA reductase in hamsters fed with amaranth protein. Methodology: Amaranth protein was isolated according to the conventional isoelectric precipitation methodology. Thirty hamsters were divided in 5 groups and were fed diets with different protein source. Experimental groups (I and lcol) had a diet containing 20% of protein amaranth and control groups(C and Cool) received a diet with 20% of casein. Moreover, groups \"col\" had also a diet with 0.1% cholesterol and 13.5% coconut oil in their composition. The lipid metabolism was accompanied through monitoring of plasma concentrations of total cholesterol, triglycerides, HDL and non-HDL fraction in animals. Excretion of cholesterol and bile acids were quantified in the feces of animals and the degree of hepatic steatosis was determined by histological analysis of the liver\'s right lobe. The HMGR enzyme activity in the liver was measured by the CS 1090 Kit from Sigma-Aldrich adjusted in accordance with Cong et al, 2012. The analysis is based on spectrometry with absorbance of 340nm at 37 ° C, which represents the oxidation of NADPH by HMG-CoA reductase in the presence of HMG-CoA substrate. Conclusions: Amaranth protein can be considered as an ally in reducing of injuries generated by dyslipidemia, since it significantly reduced levels of plasma cholesterol and hepatic fat. Furthermore, it was demonstrated its effect on reducing activity of HMG-CoA reductase enzyme in hypercholesterolemic animals, which were fed with amaranth protein. Therefore, once verified the hypocholesterolemic effect of amaranth and its possible action mechanism through HMG-CoA reductase enzyme, stimuli on the production of amaranth are expected as an alternative to diversify the diet and agriculture.

Introdução: Atualmente as Doenças Crônicas não Transmissíveis (DCNTs) são um dos maiores problemas de saúde pública da sociedade. É bastante claro o papel da dieta no controle do colesterol e na incidência de doenças cardiovasculares. Neste sentido, o amaranto desperta grande interesse devido a sua propriedade hipocolesterolemizante. Estudos sugerem que seu efeito hipocolesterolemizante está associado à inibição da enzima HMG-CoA redutase, chave na síntese do colesterol endógeno. Objetivo: Avaliar a atividade enzimática hepática da HMG-CoA redutase de hamsters alimentados com proteína de amaranto. Metodologia: Trinta hamsters foram divididos em 5 grupos e receberam dieta diferenciadas pela fonte protéica. Os grupos I e Icol receberam dieta com 20% de proteína de amaranto e os grupos caseína C e Ccol receberam dieta com 20% de caseína. Os grupos \"col\" apresentavam dieta com 0,1% de colesterol e 13,5% de gordura de coco. O metabolismo lipídico foi acompanhado através do monitoramento das concentrações plasmáticas de colesterol total, triacilgliceróis, HDL, e fração não-HDL nos animais. A excreção de colesterol e ácidos biliares foram quantificados nas fezes dos animais e o grau de esteatose hepática foi determinada através de análises histológicas do lobo direito do fígado. A atividade da enzima HMGR nos fígados foi medida por meio do Kit CS 1090 da Sigma-Aldrich com adaptações segundo Cong et al, 2012. A análise é baseada em espectrometria com absorbância de 340nm a 37ºC, que representa a oxidação de NADPH pela HMG-CoA redutase, na presença do substrato HMG-CoA. Conclusões: A proteína de amaranto pode ser considerado um aliado na redução dos agravos gerados pela dislipidemia, uma vez que reduziu significativamente os níveis de colesterol plasmático e gordura hepática, além de ser demonstrado seu efeito na redução da atividade da enzima HMG-CoA redutase dos animais hipercolesterolemizados que se alimentaram com proteína de amaranto. Uma vez verificado o efeito hipocolesterolemizante e seu possível mecanismo de ação por meio da enzima HMG-CoA redutase, espera-se com isso, estimular o consumo pela população brasileira produção de amaranto no Brasil, como alternativa para diversificar a dieta e a agricultura. / Introduction: Nowadays, Non-Communicable Chronic Diseases (NCCD) are a major challenge in health public. It is evident the role of diet in the control of cholesterol and incidence of cardiovascular disease. In this sense, amaranth arouses great interest due to its hypocholesterolemic property. Studies suggest that amaranth\'s hypocholesterolemic effect is associated with the inhibition of the enzyme HMG-CoA reductase, known as the key process to the endogenous cholesterol synthesis. Objective: Evaluate the hepatic enzymatic activity of HMG-CoA reductase in hamsters fed with amaranth protein. Methodology: Amaranth protein was isolated according to the conventional isoelectric precipitation methodology. Thirty hamsters were divided in 5 groups and were fed diets with different protein source. Experimental groups (I and lcol) had a diet containing 20% of protein amaranth and control groups(C and Cool) received a diet with 20% of casein. Moreover, groups \"col\" had also a diet with 0.1% cholesterol and 13.5% coconut oil in their composition. The lipid metabolism was accompanied through monitoring of plasma concentrations of total cholesterol, triglycerides, HDL and non-HDL fraction in animals. Excretion of cholesterol and bile acids were quantified in the feces of animals and the degree of hepatic steatosis was determined by histological analysis of the liver\'s right lobe. The HMGR enzyme activity in the liver was measured by the CS 1090 Kit from Sigma-Aldrich adjusted in accordance with Cong et al, 2012. The analysis is based on spectrometry with absorbance of 340nm at 37 ° C, which represents the oxidation of NADPH by HMG-CoA reductase in the presence of HMG-CoA substrate. Conclusions: Amaranth protein can be considered as an ally in reducing of injuries generated by dyslipidemia, since it significantly reduced levels of plasma cholesterol and hepatic fat. Furthermore, it was demonstrated its effect on reducing activity of HMG-CoA reductase enzyme in hypercholesterolemic animals, which were fed with amaranth protein. Therefore, once verified the hypocholesterolemic effect of amaranth and its possible action mechanism through HMG-CoA reductase enzyme, stimuli on the production of amaranth are expected as an alternative to diversify the diet and agriculture.