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Objective: HDL (high-density lipoprotein) role in atherosclerosis is controversial. Clinical trials with CETP (cholesterylester transfer protein)-inhibitors have not provided benefit. We have shown that HDL remodeling in hypercholesterolemia reduces HDL cardioprotective potential. We aimed to assess whether hypercholesterolemia affects HDL-induced atherosclerotic plaque regression. Approach and Results: Atherosclerosis was induced in New Zealand White rabbits for 3-months by combining a high-fat-diet and double-balloon aortic denudation. Then, animals underwent magnetic resonance imaging (basal plaque) and randomized to receive 4 IV infusions (1 infusion/wk) of HDL isolated from normocholesterolemic (NC-HDL; 75 mg/kg; n=10), hypercholesterolemic (HC-HDL; 75 mg/Kg; n=10), or vehicle (n=10) rabbits. Then, animals underwent a second magnetic resonance imaging (end plaque). Blood, aorta, and liver samples were obtained for analyses. Follow-up magnetic resonance imaging revealed that NC-HDL administration regressed atherosclerotic lesions by 4.3%, whereas, conversely, the administration of HC-HDLs induced a further 6.5% progression (P

Introduction and objectives Little is known about the characteristics of persons with familial hypercholesterolemia (FH) younger than 18 years, the lipid-lowering therapy used in these patients, and the lipid goals reached in real life. Our aim was to evaluate the achievement of low-density lipoprotein cholesterol (LDL-C) treatment goals in FH patients younger than 18 years enrolled in a large national registry. Methods We analyzed patients younger than 18 years enrolled in a large ongoing registry of molecularly-defined patients with FH in Spain. The attainment of guideline-recommended plasma LDL-C goals at entry and follow-up was analyzed in relation to the use of lipid-lowering therapy. Results We enrolled 392 individuals younger than 18 years. Of these, 217 were molecularly-diagnosed FH patients and had a complete follow-up. The median follow-up time was 4.69 years (interquartile range, 2.48-6.38 years), 68.2% of FH patients were on statins, and 41.5% patients had LDL-C < 130 mg/dL. Statin use was the only predictor of LDL-C goal attainment. Conclusions This study shows that a high proportion of FH patients younger than 18 years have high LDL-C levels and fail to achieve recommended LDL-C targets. Statin use was the only independent predictor of LDL-C goal achievement. No safety concerns were detected during follow-up. These results indicate that many FH patients are not adequately controlled and that there is still room for treatment improvement. Full English text available from: www.revespcardiol.org/en © 2016 Sociedad Española de Cardiología

Aims Statins inhibit oxidative stress, but the interplay between cholesterol lowering and antioxidant vitamins is still unclear. Aims of the study were to assess if statins inhibit oxidative stress independently from cholesterol lowering, to assess the behaviour of vitamin E simultaneously with the changes of oxidative stress, to determine in vitro if atorvastatin was able to directly influence platelet-mediated LDL oxidation and vitamin E consumption. Methods and results In 30 hypercholesterolaemic patients (HC) and 20 healthy subjects (HS), urinary isoprostanes and plasma vitamin E were determined. The HC were randomized to diet or diet plus atorvastatin 10 mg/day. Compared with HS, HC had higher isoprostanes and lower vitamin E levels. The statin-allocated group showed a reduction of isoprostanes after only 3 days (-18.8%, P < 0.01); after 30 days, a stronger reduction of isoprostanes was noted (-37.1%, P < 0.01) whereas an increase of vitamin E (+42%, P < 0.01) and a reduction of cholesterol (-24.9%, P < 0.01) were observed. The diet-allocated group showed a weak decrease of cholesterol after 30 days. In vitro study showed that atorvastatin dose-dependently inhibited platelet-mediated LDL oxidation and isoprostane formation with a mechanism involving NADPH-oxidase. Conclusion The study provides the first evidence that atorvastatin exerts an early antioxidant effect that could contribute to enhancing circulating vitamin E.

1-{7-[(1-(3,5-Diethoxyphenyl)-3-{[(3,5-difluorophenyl)(ethyl)amino]carbo nyl}-4-oxo-1,4-dihydroquinolin-7-yl)oxy]heptyl}-1-methylpiperidinium bromide, R-146224, is a potent, specific ileum apical sodium-dependent bile acid transporter (ASBT) inhibitor; concentrations required for 50% inhibition of [3H]taurocholate uptake in human ASBT-expressing HEK-293 cells and hamster ileum tissues were 0.023 and 0.73 μM, respectively. In bile-fistula rats, biliary and urinary excretion 48 h after 10 mg/kg [14C]R-146224, were 1.49 ± 1.75% and 0.14 ± 0.05%, respectively, demonstrating extremely low absorption. In hamsters, R-146224 dose-dependently reduced gallbladder bile [3H]taurocholate uptake (ED50: 2.8 mg/kg). In basal diet-fed hamsters, 14-day 30-100 mg/kg R-146224 dose-dependently reduced serum total cholesterol (∼ 40%), high density lipoprotein (HDL) cholesterol (∼ 37%), non-HDL cholesterols (∼ 20%), and phospholipids (∼ 20%), without affecting serum triglycerides, associated with reduced free and esterified liver cholesterol contents. In normocholesterolemic cynomolgus monkeys, R-146224 specifically reduced non-HDL cholesterol. In human ileum specimens, R-146224 dose-dependently inhibited [3H]taurocholate uptake. Potent non-systemic ASBT inhibitor R-146224 decreases bile acid reabsorption by inhibiting the ileal bile acid active transport system, resulting in hypolipidemic activity. © 2006 Elsevier B.V. All rights reserved. Chemicals / CAS: carbon 14, 14762-75-5; cholesterol, 57-88-5; taurocholic acid, 145-42-6, 59005-70-8, 81-24-3; tritium, 10028-17-8; carrier protein, 80700-39-6; sodium, 7440-23-5; 1-(7-((1-(3,5-diethoxyphenyl)-3-(((3,5-difluorophenyl)(ethyl)amino)carbonyl)-4-oxo-1,4-dihydroquinolin-7-yl)oxy)heptyl)-1-methylpiperidinium bromide; Anticholesteremic Agents; Bile Acids and Salts; Cholesterol, 57-88-5; Membrane Transport Proteins; Organic Anion Transporters, Sodium-Dependent; Piperidines; Quinolines; Sodium, 7440-23-5; sodium-bile acid cotransporter, 145420-23-1; Symporters; Taurocholic Acid, 81-24-3

Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-27T11:20:33Z No. of bitstreams: 0Bitstream added on 2014-05-27T14:39:43Z : No. of bitstreams: 1 2-s2.0-0038048845.pdf: 4251947 bytes, checksum: c052a2306aa5768052f92319e9325e90 (MD5) Made available in DSpace on 2014-05-27T11:20:33Z (GMT). No. of bitstreams: 0 Previous issue date: 2002-12-01 The purpose of this study was to evaluate the effects of simvastatin on guided bone regeneration in the mandibles of ovariectomized rats, and to observe their blood cholesterol levels. Seventy female rats were divided into two groups: control and treated, both groups containing normal and ovariectomized rats. A month after ovariectomy a bone defect was created in the mandible, and was covered by a polytetrafluoroethylene membrane. The treated groups received simvastatin orally for 15 or 30 days. The rats were sacrificed 15, 30 or 60 days after surgery, at which time a blood sample was extracted for blood cholesterol level analysis and the mandible was extracted for densitometric, histological and morphometric analysis. All specimens underwent analysis of variance. The ovariectomized animals had higher cholesterol levels than the treated normal animals, and no significant difference was found between the different treatment periods and the sacrifice times. The densitometric, histological and morphometric analysis showed that the treated ovariectomized animals developed more new bone than the control ovariectomized rats, but no significant difference was observed between the treatment periods. It can be concluded that the deficiency of estrogen increased the level of blood cholesterol and that the simvastatin aided new bone formation in the ovariectomized animals.

Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-27T11:26:22Z No. of bitstreams: 0Bitstream added on 2014-05-27T14:42:08Z : No. of bitstreams: 1 2-s2.0-84855735783.pdf: 253894 bytes, checksum: aa6e10598143e65f3b3b72ba84ed4e65 (MD5) Made available in DSpace on 2014-05-27T11:26:22Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-01-16 Background: There is increasing interest in non-pharmacological control of cholesterol and triglyceride levels in the plasma and diet-drug association represent an important area of studies. The objective of this study was to observe the hypocholesterolemic effect of soybean β-conglycinin (7S protein) alone and combined with fenofibrate and rosuvastatin, two hypolipidemic drugs. Methods. The protein and drugs were administered orally once a day to rats and the effects were evaluated after 28 days. Wistar rats were divided into six groups (n = 9): hypercholesterolemic diet (HC), HC+7S protein (300 mg.kg-1 day-1) (HC-7S), HC+fenofibrate (30 mg.kg-1 day-1)(HC-FF), HC+rosuvastatin (10 mg.kg-1 day-1)(HC-RO), HC+7S+fenofibrate (HC-7S-FF) and HC+7S+rosuvastatin (HC-7S-RO). Results: Animals in HC-7S, HC-FF and HC-RO exhibited reductions of 22.9, 35.8 and 18.8% in total plasma cholesterol, respectively. In HC-7S-FF, animals did not show significant alteration of the level in HC+FF while the group HC-7S-RO showed a negative effect in comparison with groups taking only protein (HC-7S) or drug (HC-RO). The administration of the protein, fenofibrate and rosuvastatin alone caused increases in the plasma HDL-C of the animals, while the protein-drug combinations led to an increase compared to HC-FF and HC-RO. The plasma concentration of triacylgycerides was significantly reduced in the groups without association, while HC-7S-FF showed no alteration and HC-7S-RO a little reduction. Conclusion: The results of our study indicate that conglycinin has effects comparable to fenofibrate and rosuvastatin on the control of plasma cholesterol, HDL-C and triacylglycerides, when given to hypercholesterolemic rats, and suggests that the association of this protein with rosuvastatin alters the action of drug in the homeostasis of cholesterol. © 2012 Ferreira et al; licensee BioMed Central Ltd. Department of Food and Nutrition School of Pharmaceutical Sciences São Paulo State University-UNESP, Araraquara, SP Department of Food and Nutrition School of Pharmaceutical Sciences São Paulo State University-UNESP, Araraquara, SP

Objective: To evaluate the efficacy and safety of colesevelam in Hispanic subjects with primary hyperlipidemia and prediabetes. Materials and Methods: A 16-week, randomized, double-blind, placebo-controlled, multinational study evaluating colesevelam in participants with primary hyperlipidemia (low-density lipoprotein cholesterol [LDL-C] level > 100 mg/dL) and prediabetes (fasting plasma glucose level > 110 to less than 125 mg/dL, or 2-hour postload glucose level > 140 to less than 200 mg/dL during an oral glucose tolerance test) was conducted between January 14, 2008 and April 3, 2009. Participants were randomized 1:1 to colesevelam 3.75 g/day or placebo. The primary efficacy endpoint was mean change from baseline in LDL-C level with colesevelam compared with placebo. Participants who self-identifed as Hispanic during enrollment were included in this exploratory analysis evaluating the effcacy of colesevelam in Hispanics with primary hyperlipidemia and prediabetes. Results: From a total of 216 subjects with primary hyperlipidemia and prediabetes, 153 Hispanics were included in this post hoc analysis; 77 subjects were randomized to colesevelam and 76 subjects were randomized to placebo. At week 16, LDL-C levels were significantly reduced with colesevelam compared with placebo (mean treatment difference, -19.4%; P less than 0.0001). Achievement of LDL-C level less than 100 mg/dL was more frequent with colesevelam than with placebo (27% vs 11%; P = 0.002). In addition, significant mean reductions in non-high-density lipoprotein cholesterol, total cholesterol, and apolipoprotein B levels (P less than 0.0002 for all), and a significant median increase in triglyceride levels (P = 0.003), were seen with colesevelam compared with placebo. At study end, there was a significant mean reduction in glycated hemoglobin levels and median reduction in fasting plasma glucose levels with colesevelam compared with placebo (P less than 0.02 for both). A fasting plasma glucose level less than 100 mg/dL was achieved in 44% of colesevelam recipients compared with 23% of placebo recipients (P less than 0.05). Overall, colesevelam was well tolerated. Conclusion: Colesevelam may be a treatment option for Hispanic subjects with primary hyperlipidemia and prediabetes, mainly to reduce LDL-C levels, with added beneficial effect on glucose levels. © Postgraduate Medicine.

Objective: To evaluate initial combination therapy with metformin plus colesevelam in drug-naïve Hispanic patients with type 2 diabetes mellitus. Research Design and Methods: Patients self-identifed as Hispanic from a previous study were included in this exploratory post hoc analysis. Patients were randomized to metformin plus colesevelam or metformin plus placebo. The primary effcacy parameter was the mean change in glycated hemoglobin (HbA1c) levels from baseline. Results: Metformin plus colesevelam had a greater mean HbA1c reduction (-1.2 ± 0.1%) than metformin plus placebo (-0.8 ± 0.1%; P = 0.001) from mean baselines of 7.7% and 7.6%, respectively. Low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, total cholesterol, and apolipoprotein (apo) B levels were also reduced (P and lt; 0.0001 for all), while triglyceride (P and lt; 0.0001) and apoA-I (P and lt; 0.05) levels were increased with metformin plus colesevelam treatment compared with metformin plus placebo. With metformin plus colesevelam versus metformin plus placebo, more patients achieved an HbA1c of, 7.0% (75% vs 56%) and LDL-C of, 100 mg/dL (49% vs 14%; both P, 0.05). Conclusion: Metformin plus colesevelam may be an effective initial treatment option for Hispanic patients with early type 2 diabetes mellitus. © Postgraduate Medicine.

The aim of this study was to define the anti-atherosclerotic role of liver-X-receptors (LXRs) under lesion progressive and lesion regressive conditions, to establish a temporal line of events, and to gain insights into the mechanisms underlying the anti-atherogenic potency of LXRs. We used apoE*3Leiden (E3L) mice to comprehensively and time-dependently dissect how T0901317, an LXR-agonist, inhibits initiation and progression of atherosclerotic lesions and regresses existing lipid- and macrophage-rich lesions. T0901317 suppresses lesion evolution and promotes lesion regression regarding lesion number, area, and severity. Quantitative plasma and vessel wall analyses corroborated by immunohistochemical evaluation of the aortic lesions revealed that under progressive (high-cholesterol diet) as well as regressive (cholesterol-free diet) conditions T0901317: i) significantly increases plasma triglyceride and total cholesterol levels; ii) does not affect the systemic inflammation marker, Serum amyloid A (SAA); iii) suppresses endothelial monocyte adhesion; and iv) induces the expression of the cholesterol efflux-related genes apolipoprotein E (apoE), ATP binding cassette (ABC) transporters ABCA1 and ABCG1. Furthermore, under progressive conditions, T0901317 suppresses the vascular inflammatory status (NF-κB) and the vascular expression of adhesion molecules [E-selectin, intercellular adhesion molecule (ICAM)-1, and CD44], lowers lesional macrophage accumulation, and blocks lesion evolution at the transition from lesional stage II to III. Under regressive conditions, T0901317 induces lesional macrophage disappearance and increases the expression of the chemokine receptor CCR7, a factor functionally required for regression. The LXR-agonist T0901317 retards vascular lesion development and promotes lesion regression at several levels. The findings support that vascular LXR is a potential anti-atherosclerotic target. Copyright © 2009 by the American Society for Biochemistry and Molecular Biology, Inc.

The aim of this study was to define the anti-atherosclerotic role of liver-X-receptors (LXRs) under lesion progressive and lesion regressive conditions, to establish a temporal line of events, and to gain insights into the mechanisms underlying the anti-atherogenic potency of LXRs. We used apoE*3Leiden (E3L) mice to comprehensively and time-dependently dissect how T0901317, an LXR-agonist, inhibits initiation and progression of atherosclerotic lesions and regresses existing lipid- and macrophage-rich lesions. T0901317 suppresses lesion evolution and promotes lesion regression regarding lesion number, area, and severity. Quantitative plasma and vessel wall analyses corroborated by immunohistochemical evaluation of the aortic lesions revealed that under progressive (high-cholesterol diet) as well as regressive (cholesterol-free diet) conditions T0901317: i) significantly increases plasma triglyceride and total cholesterol levels; ii) does not affect the systemic inflammation marker, Serum amyloid A (SAA); iii) suppresses endothelial monocyte adhesion; and iv) induces the expression of the cholesterol efflux-related genes apolipoprotein E (apoE), ATP binding cassette (ABC) transporters ABCA1 and ABCG1. Furthermore, under progressive conditions, T0901317 suppresses the vascular inflammatory status (NF-κB) and the vascular expression of adhesion molecules [E-selectin, intercellular adhesion molecule (ICAM)-1, and CD44], lowers lesional macrophage accumulation, and blocks lesion evolution at the transition from lesional stage II to III. Under regressive conditions, T0901317 induces lesional macrophage disappearance and increases the expression of the chemokine receptor CCR7, a factor functionally required for regression. The LXR-agonist T0901317 retards vascular lesion development and promotes lesion regression at several levels. The findings support that vascular LXR is a potential anti-atherosclerotic target. Copyright © 2009 by the American Society for Biochemistry and Molecular Biology, Inc.

1-{7-[(1-(3,5-Diethoxyphenyl)-3-{[(3,5-difluorophenyl)(ethyl)amino]carbo nyl}-4-oxo-1,4-dihydroquinolin-7-yl)oxy]heptyl}-1-methylpiperidinium bromide, R-146224, is a potent, specific ileum apical sodium-dependent bile acid transporter (ASBT) inhibitor; concentrations required for 50% inhibition of [3H]taurocholate uptake in human ASBT-expressing HEK-293 cells and hamster ileum tissues were 0.023 and 0.73 μM, respectively. In bile-fistula rats, biliary and urinary excretion 48 h after 10 mg/kg [14C]R-146224, were 1.49 ± 1.75% and 0.14 ± 0.05%, respectively, demonstrating extremely low absorption. In hamsters, R-146224 dose-dependently reduced gallbladder bile [3H]taurocholate uptake (ED50: 2.8 mg/kg). In basal diet-fed hamsters, 14-day 30-100 mg/kg R-146224 dose-dependently reduced serum total cholesterol (∼ 40%), high density lipoprotein (HDL) cholesterol (∼ 37%), non-HDL cholesterols (∼ 20%), and phospholipids (∼ 20%), without affecting serum triglycerides, associated with reduced free and esterified liver cholesterol contents. In normocholesterolemic cynomolgus monkeys, R-146224 specifically reduced non-HDL cholesterol. In human ileum specimens, R-146224 dose-dependently inhibited [3H]taurocholate uptake. Potent non-systemic ASBT inhibitor R-146224 decreases bile acid reabsorption by inhibiting the ileal bile acid active transport system, resulting in hypolipidemic activity. © 2006 Elsevier B.V. All rights reserved. Chemicals / CAS: carbon 14, 14762-75-5; cholesterol, 57-88-5; taurocholic acid, 145-42-6, 59005-70-8, 81-24-3; tritium, 10028-17-8; carrier protein, 80700-39-6; sodium, 7440-23-5; 1-(7-((1-(3,5-diethoxyphenyl)-3-(((3,5-difluorophenyl)(ethyl)amino)carbonyl)-4-oxo-1,4-dihydroquinolin-7-yl)oxy)heptyl)-1-methylpiperidinium bromide; Anticholesteremic Agents; Bile Acids and Salts; Cholesterol, 57-88-5; Membrane Transport Proteins; Organic Anion Transporters, Sodium-Dependent; Piperidines; Quinolines; Sodium, 7440-23-5; sodium-bile acid cotransporter, 145420-23-1; Symporters; Taurocholic Acid, 81-24-3

The purpose of this study was to evaluate the effects of simvastatin, by oral or subcutaneous administration, on tibial defects regeneration and blood cholesterol level in rats. A surgical defect was made on the right tibia of 40 male animals assigned to 4 groups (n=10), based on two routes of administration and on the use or not of simvastatin: subcutaneous injection of simvastatin (7 mg/kg) (group AT) or only the vehicle of drug suspension (group AC), above the defect area, for 5 days; and 20 mg/kg of simvastatin macerated on water (group BT) or only water (group BC), orally, daily, during the whole observation period. The animals were sacrificed after 15 or 30 days, when blood samples were analyzed to check plasma cholesterol levels. Tibiae were removed and, after decalcification and routine laboratorial processing, histological and histomorphometrical analyses were carried out. ANOVA was used for statistical analysis at 5% signficance level. The histological and histomorphometrical analyses showed significant differences only between the experimental periods (p0.05) for blood cholesterol levels between the groups. In conclusion, simvastatin administration either orally or subcutaneously did not improve bone repair of experimental tibial defects and did not alter blood cholesterol levels in rats. Este estudo avaliou a influência da sinvastatina, administrada por via oral ou subcutânea, na reparação de defeitos ósseos em tíbia e nos níveis de colesterol sangüíneo, em ratos. Foram realizados defeitos cirúrgicos nas tíbias direitas de 40 ratos machos, distribuídos em 4 grupos (n=10), tomando-se como base duas vias de administração e o uso ou não de sinvastatina: injeção subcutânea de sinvastatina (7 mg/kg) (grupo AT) ou apenas do veículo de suspensão da droga (grupo AC), sobre a região do defeito, durante 5 dias; 20 mg/kg de sinvastatina (grupo BT) ou água filtrada (grupo BC) via oral, diariamente, durante todo o período de observação. Os animais foram sacrificados após 15 ou 30 dias, quando amostras sangüíneas foram colhidas para análise do nível de colesterol. As tíbias foram removidas e, após descalcificação e procedimentos laboratoriais de rotina, procedeu-se à análise histológica e histomorfométrica. Para avaliação estatística utilizou-se ANOVA com nível de significância de 5%. As análises histomorfométrica e histológica mostraram diferença entre os grupos apenas com relação ao período experimental (p0,05). Concluiu-se que, nas condições utilizadas, a sinvastatina, administrada via oral ou subcutânea, não exerceu efeito estimulador sobre o reparo ósseo de defeitos experimentais em tíbias de ratos e não alterou os níveis de colesterol sangüíneo.

Esterase plays a major role in the degradation of natural materials and industrial pollutants, viz., cereal wastes, plastics, and other toxic chemicals. It is useful in the synthesis of optically pure compounds, perfumes, and antioxidants. The potential applications of esterase with reference to agriculture, food, and pharmaceutical industries, are discussed in this review. Promising applications in this avenue can be supported by appropriate production strategies. ? Springer-Verlag 2005.

The influence of the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors pravastatin and simvastatin on lens cholesterol metabolism was investigated in the rat. Short-term organ culture experiments with explanted lenses from 21-day-old Wistar rats showed that simvastatin was at least 35 times more effective than pravastatin in inhibiting cholesterol synthesis. In vivo the cholesterol content of the rat lens increased linearly with age. Experiments were designed to answer the question whether simvastatin and pravastatin inhibit lens cholesterol synthesis in vivo, which would result in a reduced cholesterol accumulation in the lens with age. Young Wistar rats were weaned at an age of 21 days and had ad libitum access to a chow supplemented with 10-100 mg vastatin kg-1 (drug consumption: 1.5-15 mg vastatin kg-1 body weight day-1, respectively) or no additions for 3 weeks. Both drugs induced the HMG-CoA reductase activity in rat liver microsomes (isolated after 1, 2 and 3 weeks of treatment) to a similar extent. This indicates that the two drugs inhibited hepatic cholesterol synthesis to a comparable extent. During the whole treatment period no significant differences between control and drug-treated animals could be observed when the wet weight and protein content of the lenses were considered. However, a striking difference between the control group and pravastatin group (50 mg drug kg-1 diet) on the one hand and the simvastatin group (50 mg drug kg-1 diet) on the other was observed when the cholesterol content of the lenses were compared as a function of age. After 1 week of treatment all three groups showed the same increase in cholesterol content. Thereafter, the simvastatin group showed little additional increase, whereas the pravastatin group and the control group showed the same increase in cholesterol content (from 20 to 40 μg per lens). Even at a concentration of 100 mg kg-1 chow, pravastatin had no effect after 3 weeks, whereas at this concentration simvastatin already caused a reduction in lens cholesterol content after 7 days of treatment. Simvastatin in a concentration of 10 mg kg-1 chow reduced lens cholesterol by more than 2 5% after 3 weeks. So, we observed at least a ten-fold difference between both drugs in the ability to affect the cholesterol content of the lens in vivo. Furthermore, our observations indicate that in the avascular lens the accumulation of cholesterol with age is largely dependent on in situ de novo synthesis, and that under these in vivo conditions simvastatin, but not pravastatin, inhibits cholesterol synthesis in the lens. Chemicals/CAS: cholesterol, 57-88-5; pravastatin, 81131-74-0; simvastatin, 79902-63-9; Anticholesteremic Agents; Antilipemic Agents; Cholesterol, 57-88-5; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin, 75330-75-5; Pravastatin, 81093-37-0; Simvastatin, 79902-63-9

The influence of the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors pravastatin and simvastatin on lens cholesterol metabolism was investigated in the rat. Short-term organ culture experiments with explanted lenses from 21-day-old Wistar rats showed that simvastatin was at least 35 times more effective than pravastatin in inhibiting cholesterol synthesis. In vivo the cholesterol content of the rat lens increased linearly with age. Experiments were designed to answer the question whether simvastatin and pravastatin inhibit lens cholesterol synthesis in vivo, which would result in a reduced cholesterol accumulation in the lens with age. Young Wistar rats were weaned at an age of 21 days and had ad libitum access to a chow supplemented with 10-100 mg vastatin kg-1 (drug consumption: 1.5-15 mg vastatin kg-1 body weight day-1, respectively) or no additions for 3 weeks. Both drugs induced the HMG-CoA reductase activity in rat liver microsomes (isolated after 1, 2 and 3 weeks of treatment) to a similar extent. This indicates that the two drugs inhibited hepatic cholesterol synthesis to a comparable extent. During the whole treatment period no significant differences between control and drug-treated animals could be observed when the wet weight and protein content of the lenses were considered. However, a striking difference between the control group and pravastatin group (50 mg drug kg-1 diet) on the one hand and the simvastatin group (50 mg drug kg-1 diet) on the other was observed when the cholesterol content of the lenses were compared as a function of age. After 1 week of treatment all three groups showed the same increase in cholesterol content. Thereafter, the simvastatin group showed little additional increase, whereas the pravastatin group and the control group showed the same increase in cholesterol content (from 20 to 40 μg per lens). Even at a concentration of 100 mg kg-1 chow, pravastatin had no effect after 3 weeks, whereas at this concentration simvastatin already caused a reduction in lens cholesterol content after 7 days of treatment. Simvastatin in a concentration of 10 mg kg-1 chow reduced lens cholesterol by more than 2 5% after 3 weeks. So, we observed at least a ten-fold difference between both drugs in the ability to affect the cholesterol content of the lens in vivo. Furthermore, our observations indicate that in the avascular lens the accumulation of cholesterol with age is largely dependent on in situ de novo synthesis, and that under these in vivo conditions simvastatin, but not pravastatin, inhibits cholesterol synthesis in the lens. Chemicals/CAS: cholesterol, 57-88-5; pravastatin, 81131-74-0; simvastatin, 79902-63-9; Anticholesteremic Agents; Antilipemic Agents; Cholesterol, 57-88-5; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin, 75330-75-5; Pravastatin, 81093-37-0; Simvastatin, 79902-63-9

This paper describes the direct examination of HMG CoA reductase activity in rats treated with 20,25-diazacholesterol. Conversion of acetyl CoA and HMG CoA to mevalonate increased to over 200% of control values in the microsomes and in the 12,000 g supernatant of liver homogenates after 5 days of treatment. The time course of induction coincided with the development of hypocholesterolemia. Animal weights, liver weights, and microsomal protein content did not vary significantly between animal groups. Incubations to which the compound was introduced in vitro in concentrations as great as 0.5 m M produced no significant difference from control incubations. Similar treatment of the animals with 7-ketocholesterol, a cholesterol derivative reported to repress HMG CoA reductase activity in tissue cultures, produced no appreciable difference in reductase activity or serum steroid levels in vivo.

Scientific progress has shown the involvement of diet in a large number of diseases and disorders (e.g. colon cancer, cardiovascular disorders, diabetes mellitus type 2, a number of inflammation related health problems, etc.). This triggered the introduction of functional foods, dietary components with “added health value”. So far, only a few successful products were launched (cholesterol lowering stannols, probiotics, a number of specific fatty acids), and most of these functional foods had great difficulty to obtain scientific proof of efficacy. Why does nutritional science have such a hard job in providing evidence for health claims related to dietary components? Unlike pharmacological and biomedical research, where bioactive compounds are developed to treat a well-characterized disease, nutrition deals with prevention of disease and optimization of health. Biomarkers that quantify the health status essentially are missing, and much of the nutrition research (the large observational and intervention cohorts) relies on disease endpoints instead of health endpoints. Also in the “golden standard” of nutrition and health research, the crossover dietary intervention studies, the quantification of the effect is a major issue. Usually, the observed effects are minor and great efforts have to be made to unravel treatment related health effect from the confounding parameters. In other words, the confounding parameters have a large impact. The recent “omics”-related observations in human intervention studies confirm that intra-individual variation is much smaller than inter-individual variation. Differences between study subjects may be much larger than differences directly related to dietary treatment. The keys for personalized nutrition actually are these “confounders” that make the life of nutritional scientists so difficult. Age, gender, life style (e.g. exercise), phenotype (e.g. body mass index), genetic make-up and epi-genomic imprinting all possibly determine our nutritional needs, the way we respond to nutrition, and thus our “personal diet-and-health relationship”. Infant nutrition clearly differs from sports-diet. Now, the question is two faceted: To what extent is this personal diet- and health-relationship practically valid; How can nutritional science demonstrate this? My personal opinion is that indeed this relationship exists to a much greater extent than assumed until now, and that nutritional science will need to do a much better job in accurately identifying and quantifying the subtle differences in health status related to dietary treatment. A complete merge of nutrition with a number of fundamental scientific disciplines (molecular biology, biochemistry, bioinformatics, statistics, etc.) will be essential here. Most disorders related to nutrition are packed with genetic variation, but the effect of nutritional modulation of the phenotypic outcome of these variations is difficult to assess as yet. Nutrition is the worst case scenario for this approach in science: multiple minor genetic differences possibly modulated by multiple food bioactives, usually with low receptor affinity, resulting in multiple minor changes in gene expression and resulting phenotypic expression. Many nutritional crossover intervention studies did not provide the expected results; primarily due to the large inter individual differences in results. Again, the “confounders” kill the study. Inclusion of the genetic component causes financial and ethical problems, as (depending on the frequency and complexity of the haplotype) a big effort needs to be made in subject selection. Unexpected complications like ethnic genetic diversity now appear to be a major problem in the famous EU-funded multi-center studies. On top of this, bioinformatics and biostatistics needs to be further developed to meet this new type of approach. In other words, some work to be done. A second major bottleneck in the nutrition and (personalized) health relationship is the inadequacy to determine effects. We all know (or suppose?) that nutrition is related to diseases and disorders. However, we fail to measure the correct effect. Slowly, we now begin to realize that between the nutritional impact on daily homeostasis and the disease (endpoints), a separate layer of “overarching processes” both controls health and drives disease onset. Think about metabolic stress, inflammatory stress, and oxidative stress. These processes are both complex and interacting. Also, they are controlled by “setpoints” adding an additional complexity related to neurology, endocrinology and epigenomics. It might be worthwhile to revisit these “overarching processes” once we have a better grip on nutritional systems biology, i.e. the ability to study these processes both in molecular detail and in their relationship, embedded in molecular physiology. Nutritional science may and very likely eventually will determine a large number of personalized nutrition and health relationships. However, this is only a small part of the equation. Food consumption nowadays is hardly related to health, but much more to convenience. “Food is pleasure” rightfully is the credo and science will have a hard job in promoting healthy diet if this aspect is compromised. So, a personalized diet needs to be both optimized towards personal health and personal convenience. What a challenge!