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Yang Y, Xia J, Yu T, Wan S, Zhou Y, Sun G. Effects of phytosterols on cardiovascular risk factors: A systematic review and meta-analysis of randomized controlled trials. Phytother Res 2025; 39:3-24. [PMID: 39572895 DOI: 10.1002/ptr.8308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 06/20/2024] [Accepted: 07/20/2024] [Indexed: 01/21/2025]
Abstract
Cardiovascular diseases are the major cause of death globally. The primary risk factors are high blood lipid levels, hypertension, diabetes, and obesity. Phytosterols are naturally occurring plant bioactive substances. Short-term clinical trials have demonstrated phytosterols' cholesterol-lowering potential, but their effects on cardiovascular risk factors remain controversial, and relevant meta-analyses are limited and incomplete. We conducted a systematic and comprehensive search of PubMed, Web of Science, Embase and Cochrane Library up to December 22, 2023. A total of 109 randomized controlled trials (RCTS) of phytosterols (PS) intervention on cardiovascular risk factor outcomes were included in a preliminary screening of the retrieved literature by Endnote 20. We assessed the quality of all included randomized controlled trials using the Cochrane Collaboration's Risk of Bias tool. Cochrane data conversion tool was used for data conversion, and finally Stata was used for meta-analysis, egger test and sensitivity analysis of the included studies. The results indicated that dietary phytosterols intake could significantly decrease total cholesterol (TC) level (mean difference = -13.41; 95% confidence interval [CI]: -15.19, -11.63, p < 0.001), low density lipoprotein cholesterol (LDL-C) level (mean difference = -12.57; 95% CI: -13.87, -11.26, p < 0.001), triglycerides (TG) level (mean difference = -6.34; 95% CI: -9.43, -3.25, p < 0.001), C-reactive protein (CRP) level (mean difference = -0.05; 95% CI: -0.08, -0.01, p = 0.671), systolic blood pressure (SBP) level (mean difference = -2.10; 95% CI: -3.27, -0.9, p < 0.001), diastolic blood pressure (DBP) level (mean difference = -0.83; 95% CI: -0.58, -0.07, p = 0.032), increased high-density lipoprotein cholesterol (HDL-C) level (mean difference = 0.46; 95% CI: 0.13, 0.78, p = 0.005), but did not alter the levels of blood glucose (GLU) (mean difference = -0.44; 95% CI: -1.64, 0.76, p = 0.471), glycosylated hemoglobin, Type A1C (HbA1c) (mean difference = -0.28; 95% CI: -0.75, 0.20, p = 0.251), interleukin-6 (IL-6) (mean difference = 0.00; 95% CI: -0.02, 0.02, p = 0.980), tumor necrosis factor (TNF-α) (mean difference = 0.08; 95% CI: -0.08, 0.24, p = 0.335), oxidized low-density lipoprotein cholesterol (OXLDL-C) (standard mean difference = 0.16; 95% CI: -0.38, 0.06, p = 0.154), body mass index (BMI) (mean difference = 0.01; 95% CI: -0.07, 0.09, p = 0.886), waist circumference (WC) (mean difference = -0.10; 95% CI: -0.50, 0.30, p = 0.625) and body weight (mean difference = 0.03; 95% CI: -0.18, 0.24, p = 0.787). Our results suggest that phytosterols may be beneficial in reducing the levels of TC, LDL-C, TG, CRP, SBP, and DBP, but have no significant effect on GLU, HbA1c, TNF-α, IL-6, OXLDL-C, BMI, WC, and Weight. However, there were a small number of RCTS included in this study and their small population size may have reduced the quality of the study. And most of the included studies were short-term intervention trials. Therefore, higher quality studies need to be designed in future studies to establish more accurate conclusions.
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Affiliation(s)
- Yanhong Yang
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, People's Republic of China
- Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, People's Republic of China
| | - Jiayue Xia
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, People's Republic of China
- Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, People's Republic of China
| | - Tingqing Yu
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, People's Republic of China
- Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, People's Republic of China
| | - Shiyun Wan
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, People's Republic of China
- Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, People's Republic of China
| | - Yajie Zhou
- Nanjing Zhongke Pharmaceutical Co. Ltd, Nanjing, People's Republic of China
| | - Guiju Sun
- Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, People's Republic of China
- Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, People's Republic of China
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de Souza Goncalves B, Sangani D, Nayyar A, Puri R, Irtiza M, Nayyar A, Khalyfa A, Sodhi K, Pillai SS. COVID-19-Associated Sepsis: Potential Role of Phytochemicals as Functional Foods and Nutraceuticals. Int J Mol Sci 2024; 25:8481. [PMID: 39126050 PMCID: PMC11312872 DOI: 10.3390/ijms25158481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 07/30/2024] [Accepted: 08/01/2024] [Indexed: 08/12/2024] Open
Abstract
The acute manifestations of coronavirus disease 2019 (COVID-19) exhibit the hallmarks of sepsis-associated complications that reflect multiple organ failure. The inflammatory cytokine storm accompanied by an imbalance in the pro-inflammatory and anti-inflammatory host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to severe and critical septic shock. The sepsis signature in severely afflicted COVID-19 patients includes cellular reprogramming and organ dysfunction that leads to high mortality rates, emphasizing the importance of improved clinical care and advanced therapeutic interventions for sepsis associated with COVID-19. Phytochemicals of functional foods and nutraceutical importance have an incredible impact on the healthcare system, which includes the prevention and/or treatment of chronic diseases. Hence, in the present review, we aim to explore the pathogenesis of sepsis associated with COVID-19 that disrupts the physiological homeostasis of the body, resulting in severe organ damage. Furthermore, we have summarized the diverse pharmacological properties of some potent phytochemicals, which can be used as functional foods as well as nutraceuticals against sepsis-associated complications of SARS-CoV-2 infection. The phytochemicals explored in this article include quercetin, curcumin, luteolin, apigenin, resveratrol, and naringenin, which are the major phytoconstituents of our daily food intake. We have compiled the findings from various studies, including clinical trials in humans, to explore more into the therapeutic potential of each phytochemical against sepsis and COVID-19, which highlights their possible importance in sepsis-associated COVID-19 pathogenesis. We conclude that our review will open a new research avenue for exploring phytochemical-derived therapeutic agents for preventing or treating the life-threatening complications of sepsis associated with COVID-19.
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Affiliation(s)
- Bruno de Souza Goncalves
- Department of Surgery, Internal Medicine and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA; (B.d.S.G.); (D.S.); (R.P.); (M.I.); (A.N.); (A.K.); (K.S.)
| | - Darshan Sangani
- Department of Surgery, Internal Medicine and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA; (B.d.S.G.); (D.S.); (R.P.); (M.I.); (A.N.); (A.K.); (K.S.)
| | - Aleen Nayyar
- Department of Medicine, Sharif Medical and Dental College, Lahore 55150, Pakistan;
| | - Raghav Puri
- Department of Surgery, Internal Medicine and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA; (B.d.S.G.); (D.S.); (R.P.); (M.I.); (A.N.); (A.K.); (K.S.)
| | - Mahir Irtiza
- Department of Surgery, Internal Medicine and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA; (B.d.S.G.); (D.S.); (R.P.); (M.I.); (A.N.); (A.K.); (K.S.)
| | - Asma Nayyar
- Department of Surgery, Internal Medicine and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA; (B.d.S.G.); (D.S.); (R.P.); (M.I.); (A.N.); (A.K.); (K.S.)
| | - Abdelnaby Khalyfa
- Department of Surgery, Internal Medicine and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA; (B.d.S.G.); (D.S.); (R.P.); (M.I.); (A.N.); (A.K.); (K.S.)
| | - Komal Sodhi
- Department of Surgery, Internal Medicine and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA; (B.d.S.G.); (D.S.); (R.P.); (M.I.); (A.N.); (A.K.); (K.S.)
| | - Sneha S. Pillai
- Department of Surgery, Internal Medicine and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA; (B.d.S.G.); (D.S.); (R.P.); (M.I.); (A.N.); (A.K.); (K.S.)
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Barkas F, Bathrellou E, Nomikos T, Panagiotakos D, Liberopoulos E, Kontogianni MD. Plant Sterols and Plant Stanols in Cholesterol Management and Cardiovascular Prevention. Nutrients 2023; 15:2845. [PMID: 37447172 DOI: 10.3390/nu15132845] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 06/19/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023] Open
Abstract
Atherosclerotic cardiovascular disease (ASCVD) remains the major mortality cause in developed countries with hypercholesterolaemia being one of the primary modifiable causes. Lifestyle intervention constitutes the first step in cholesterol management and includes dietary modifications along with the use of functional foods and supplements. Functional foods enriched with plant sterols/stanols have become the most widely used nonprescription cholesterol-lowering approach, despite the lack of randomized trials investigating their long-term safety and cardiovascular efficacy. The cholesterol-lowering effect of plant-sterol supplementation is well-established and a potential beneficial impact on other lipoproteins and glucose homeostasis has been described. Nevertheless, experimental and human observational studies investigating the association of phytosterol supplementation or circulating plant sterols with various markers of atherosclerosis and ASCVD events have demonstrated controversial results. Compelling evidence from recent genetic studies have also linked elevated plasma concentrations of circulating plant sterols with ASCVD presence, thus raising concerns about the safety of phytosterol supplementation. Thus, the aim of this review is to provide up-to-date data on the effect of plant sterols/stanols on lipid-modification and cardiovascular outcomes, as well as to discuss any safety issues and practical concerns.
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Affiliation(s)
- Fotios Barkas
- Department of Hygiene & Epidemiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
| | - Eirini Bathrellou
- Department of Nutrition and Dietetics, School of Health Sciences and Education, Harokopio University, 17676 Kallithea, Greece
| | - Tzortzis Nomikos
- Department of Nutrition and Dietetics, School of Health Sciences and Education, Harokopio University, 17676 Kallithea, Greece
| | - Demosthenes Panagiotakos
- Department of Nutrition and Dietetics, School of Health Sciences and Education, Harokopio University, 17676 Kallithea, Greece
| | - Evangelos Liberopoulos
- 1st Propaedeutic Department of Medicine, General Hospital of Atherns 'Laiko', School of Medicine, National and Kapodistrιan University of Athens, 11527 Athens, Greece
| | - Meropi D Kontogianni
- Department of Nutrition and Dietetics, School of Health Sciences and Education, Harokopio University, 17676 Kallithea, Greece
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Abstract
Purpose of Review Coronary heart disease is the leading cause of mortality worldwide. Elevated blood cholesterol levels are not only the major but also the best modifiable cardiovascular risk factor. Lifestyle modifications which include a healthy diet are the cornerstone of lipid-lowering therapy. So-called functional foods supplemented with plant sterols lower blood cholesterol levels by about 10–15%. Recent Findings In the recent revision of the ESC/EAS dyslipidemia guideline 2019, plant sterols are recommended for the first time as an adjunct to lifestyle modification to lower blood cholesterol levels. However, the German Cardiac Society (DGK) is more critical of food supplementation with plant sterols and calls for randomized controlled trials investigating hard cardiovascular outcomes. An increasing body of evidence suggests that plant sterols per se are atherogenic. Summary This review discusses this controversy based on findings from in vitro and in vivo studies, clinical trials, and genetic evidence.
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Affiliation(s)
- Umidakhon Makhmudova
- Klinik Für Innere Medizin I, Universitätsklinikum Jena, Am Klinikum 1, 07747 Jena, Germany
| | - P. Christian Schulze
- Klinik Für Innere Medizin I, Universitätsklinikum Jena, Am Klinikum 1, 07747 Jena, Germany
| | - Dieter Lütjohann
- Institut für klinische Chemie und klinische Pharmakologie, Universitätsklinikum Bonn, Bonn, Germany
| | - Oliver Weingärtner
- Klinik Für Innere Medizin I, Universitätsklinikum Jena, Am Klinikum 1, 07747 Jena, Germany
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Moss JWE, Williams JO, Al-Ahmadi W, O'Morain V, Chan YH, Hughes TR, Menendez-Gonzalez JB, Almotiri A, Plummer SF, Rodrigues NP, Michael DR, Ramji DP. Protective effects of a unique combination of nutritionally active ingredients on risk factors and gene expression associated with atherosclerosis in C57BL/6J mice fed a high fat diet. Food Funct 2021; 12:3657-3671. [PMID: 33900312 PMCID: PMC8359826 DOI: 10.1039/d0fo02867c] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Atherosclerosis, an inflammatory disorder of the vasculature and the underlying cause of cardiovascular disease, is responsible for one in three global deaths. Consumption of active food ingredients such as omega-3 polyunsaturated fatty acids, flavanols and phytosterols has many beneficial effects on cardiovascular disease. However, their combined actions on the risk factors for atherosclerosis remains poorly understood. We have previously shown that a formulation containing each of these active components at physiologically relevant doses modulated several monocyte/macrophage processes associated with atherosclerosis in vitro, including inhibition of cytokine-induced pro-inflammatory gene expression, chemokine-driven monocyte migration, expression of M1 phenotype markers, and promotion of cholesterol efflux. The objectives of the present study were to investigate whether the protective actions of the formulation extended in vivo and to delineate the potential underlying mechanisms. The formulation produced several favourable changes, including higher plasma levels of HDL and reduced levels of macrophages and myeloid-derived suppressor cells in the bone marrow. The mRNA expression of liver-X-receptor-α, peroxisome proliferator-activated receptor-γ and superoxide dismutase-1 was induced in the liver and that of interferon-γ and the chemokine (C-X-C motif) ligand 1 decreased, thereby suggesting the potential mechanisms for many beneficial effects. Other changes were also observed such as increased plasma levels of triglycerides and lipid peroxidation that may reflect potential activation of brown fat. This study provides new insights into the protective actions and the potential underlying mechanisms of the formulation in vivo, particularly in relation to risk factors together with changes in systemic inflammation and hepatic lipid alterations associated with atherosclerosis and metabolic syndrome, and supports further assessments in human trials.
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Affiliation(s)
- Joe W E Moss
- Cardiff School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff CF10 3AX, UK.
| | - Jessica O Williams
- Cardiff School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff CF10 3AX, UK.
| | - Wijdan Al-Ahmadi
- Cardiff School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff CF10 3AX, UK.
| | - Victoria O'Morain
- Cardiff School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff CF10 3AX, UK.
| | - Yee-Hung Chan
- Cardiff School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff CF10 3AX, UK.
| | - Timothy R Hughes
- Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
| | - Juan B Menendez-Gonzalez
- European Cancer Stem Cell Research Institute, Cardiff School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK
| | - Alhomidi Almotiri
- European Cancer Stem Cell Research Institute, Cardiff School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK
| | - Sue F Plummer
- Cultech Limited, Unit 2 Christchurch Road, Baglan Industrial Park, Port Talbot, SA12 7BZ, UK
| | - Neil P Rodrigues
- European Cancer Stem Cell Research Institute, Cardiff School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK
| | - Daryn R Michael
- Cultech Limited, Unit 2 Christchurch Road, Baglan Industrial Park, Port Talbot, SA12 7BZ, UK
| | - Dipak P Ramji
- Cardiff School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff CF10 3AX, UK.
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Potential Effects of Antioxidant and Serum Cholesterol-Lowering Effects of Gynura bicolorWater Extracts in Syrian Hamster. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020. [DOI: 10.1155/2020/2907610] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Gynura bicolor(Roxb. and Willd.) DC (G. bicolor) is a dietary vegetable in the Far East. The aims of the present study were to investigate the antioxidant effects of theG. bicolorwater extract (GBWE) and its ability to regulate the blood lipid and lipoprotein profiles. In this study, the pigment composition and antioxidant ability of the GBWE were analyzed. Syrian hamsters were fed a high-fat diet (HFD) and the GBWE for 12 weeks, and the blood lipid levels, lipoprotein profiles, and cholesterol metabolism-related enzyme levels were then examined. The results showed that the GBWE exhibited excellent 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity and ferrous-ion-chelating ability. The hepatic glutathione levels in the hamsters were increased after the administration of low (0.4 g/kg BW, GBWE-L) or high (0.8 g/kg BW, GBWE-H) levels of the GBWE. The GBWE-H-treated hamsters exhibited significantly decreased serum levels of total cholesterols (TC) and low-density lipoprotein-cholesterol (LDL-C) and significantly increased levels of lectin-cholesterol acetyltransferase (LCAT). These results showed that GBWE-H can reduce the total cholesterol and LDL-C levels in HFD-fed hamsters, and this reduction might be involved in the regulation of LCAT expression.
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Poznyak AV, Silaeva YY, Orekhov AN, Deykin AV. Animal models of human atherosclerosis: current progress. ACTA ACUST UNITED AC 2020; 53:e9557. [PMID: 32428130 PMCID: PMC7266502 DOI: 10.1590/1414-431x20209557] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 02/20/2020] [Indexed: 12/24/2022]
Abstract
Atherosclerosis retains the leading position among the causes of global morbidity and mortality worldwide, especially in the industrialized countries. Despite the continuing efforts to investigate disease pathogenesis and find the potential points of effective therapeutic intervention, our understanding of atherosclerosis mechanisms remains limited. This is partly due to the multifactorial nature of the disease pathogenesis, when several factors so different as altered lipid metabolism, increased oxidative stress, and chronic inflammation act together leading to the formation and progression of atherosclerotic plaques. Adequate animal models are currently indispensable for studying these processes and searching for novel therapies. Animal models based on rodents, such as mice and rats, and rabbits represent important tools for studying atherosclerosis. Currently, genetically modified animals allow for previously unknown possibilities in modelling the disease and its most relevant aspects. In this review, we describe the recent progress made in creating such models and discuss the most important findings obtained with them to date.
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Affiliation(s)
- A V Poznyak
- Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow, Russia
| | - Y Y Silaeva
- Core Facility Centre, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
| | - A N Orekhov
- Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow, Russia
| | - A V Deykin
- Core Facility Centre, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
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Anti-Atherosclerotic Properties of Wild Rice in Low-Density Lipoprotein Receptor Knockout Mice: The Gut Microbiome, Cytokines, and Metabolomics Study. Nutrients 2019; 11:nu11122894. [PMID: 31795092 PMCID: PMC6950250 DOI: 10.3390/nu11122894] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 11/15/2019] [Accepted: 11/16/2019] [Indexed: 01/06/2023] Open
Abstract
Background and aim: We previously reported the anti-atherogenic properties of wild rice in low-density lipoprotein receptor knockout (LDL-r-KO) mice. The present study aimed to discover the mechanism of action for such effects. Materials: Fecal and plasma samples from the wild rice treated and control mice were used. Fecal bacterial population was estimated while using 16S rDNA technology. The plasma samples were used to estimate the levels of 35 inflammatory markers and metabolomics, while using Meso Scale multiplex assay and liquid chromatography-mass spectrometry (LC-MS/MS) techniques. Results: Many bacteria, particularly Anaeroplasma sp., Acetatifactor sp., and Prophyromonadaceae sp., were found in higher quantities in the feces of wild rice fed mice as compared to the controls. Cytokine profiles were significantly different between the plasma of treated and control mice. Among them, an increase in the level of IL-10 and erythropoietin (EPO) could explain the anti-atherogenic properties of wild rice. Among many metabolites tested in plasma of these animals, surprisingly, we found an approximately 60% increase in the levels of glucose in the wild rice fed mice as compared to that in the control mice. Conclusion: Additional studies warrant further investigation of the interplay among gut microbiome, inflammatory status, and macronutrient metabolism.
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Altunayar Unsalan C, Sahin I, Kazanci N. A concentration dependent spectroscopic study of binary mixtures of plant sterol stigmasterol and zwitterionic dimyristoyl phosphatidylcholine multilamellar vesicles: An FTIR study. J Mol Struct 2018. [DOI: 10.1016/j.molstruc.2018.02.100] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Dumolt JH, Radhakrishnan SK, Moghadasian MH, Le K, Patel MS, Browne RW, Rideout TC. Maternal hypercholesterolemia enhances oxysterol concentration in mothers and newly weaned offspring but is attenuated by maternal phytosterol supplementation. J Nutr Biochem 2017; 52:10-17. [PMID: 29107136 DOI: 10.1016/j.jnutbio.2017.09.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 09/02/2017] [Accepted: 09/12/2017] [Indexed: 12/17/2022]
Abstract
In hypercholesterolemic pregnancies, the maternal environment is characterized by excessive levels of atherogenic lipids that may increase cardiovascular disease risk in mothers and their offspring. We examined the influence of maternal hypercholesterolemia and phytosterol (PS) intervention on the concentration and metabolism of oxysterols, bioactive oxygenated cholesterol derivatives that regulate arterial health and lesion progression, in mothers and their newly weaned offspring. Twenty-one female apoE-/- mice were randomly assigned to three different diets throughout gestation and lactation: (1) chow, (2) high cholesterol (CH; 0.15%) and (3) CH with added PS (2%, CH/PS). At the end of the lactation period, mothers and pups were euthanized for serum and hepatic oxysterol analyses, hepatic transcriptional profiling of hepatic sterol regulatory targets and atherosclerosis. Hypercholesterolemic dams and their pups demonstrated increased (P˂.05) serum oxysterols [including 24 hydroxycholesterol (HC), 25HC, 27HC, 7αHC, 7βHC and 7 ketocholesterol)] compared with the chow group that were normalized by maternal PS supplementation. Hepatic oxysterol concentrations followed a similar pattern of response in mothers but were not altered in newly weaned pups. Hepatic mRNA expression suggested a pattern of enhanced abca1/g1 high-density-lipoprotein-mediated efflux but a reduction in biliary abcg5/g8 export in both dams and their pups. Although arterial lesions were not apparent in newly weaned pups, CH dams demonstrated enhanced atherosclerosis that was reduced upon PS intervention. These results demonstrate that offspring from hypercholesterolemic pregnancies have enhanced circulating oxysterol concentrations and highlight the potential utility of PS as a lipid-lowering option during hypercholesterolemic pregnancies for which there are currently limited options.
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Affiliation(s)
- Jerad H Dumolt
- Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA 14214
| | - Sandhya K Radhakrishnan
- Department of Biotechnical and Clinical Laboratory Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA 14214
| | - Mohammed H Moghadasian
- Department of Human Nutritional Sciences, University of Manitoba, and Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB, Canada, RH2 2A6
| | - Khuong Le
- Department of Human Nutritional Sciences, University of Manitoba, and Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, MB, Canada, RH2 2A6
| | - Mulchand S Patel
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA 14214
| | - Richard W Browne
- Department of Biotechnical and Clinical Laboratory Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA 14214
| | - Todd C Rideout
- Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA 14214.
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Lee CY, Yu MC, Perng WT, Lin CC, Lee MY, Chang YL, Lai YY, Lee YC, Kuan YH, Wei JCC, Shih HC. No additional cholesterol-lowering effect observed in the combined treatment of red yeast rice and Lactobacillus casei in hyperlipidemic patients: A double-blind randomized controlled clinical trial. Chin J Integr Med 2016; 23:581-588. [PMID: 27838874 DOI: 10.1007/s11655-016-2530-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To observe the effect of combining red yeast rice and Lactobacillus casei (L. casei) in lowering cholesterol in patients with primary hyperlipidemia, the later has also been shown to remove cholesterol in in vitro studies. METHODS A double-blind clinical trial was conducted to evaluate the cholesterol-lowering effect of the combination of red yeast rice and L. casei. Sixty patients with primary hyperlipidemia were recruited and randomized equally to either the treatment group (red yeast rice + L. casei) or the control group (red yeast rice + placebo). One red yeast rice capsule and two L. casei capsules were taken twice a day. The treatment lasted for 8 weeks, with an extended follow-up period of 4 weeks. The primary endpoint was a difference of serum low-density lipoprotein cholesterol (LDL-C) level at week 8. RESULTS At week 8, the LDL-C serum level in both groups was lower than that at baseline, with a decrease of 33.85±26.66 mg/dL in the treatment group and 38.11±30.90 mg/dL in the control group; however, there was no statistical difference between the two groups (P>0.05). The total cholesterol was also lower than the baseline in both groups, yet without a statistical difference between the two groups. The only statistically signifificant difference between the two groups was the average diastolic pressure at week 12, which dropped by 2.67 mm Hg in the treatment group and increased by 4.43 mm Hg in the placebo group (P<0.05). The antihypertensive activity may be associated with L. casei. Red yeast rice can signifificantly reduce LDL-C, total cholesterol and triglyceride. CONCLUSION The combination of red yeast rice and L. casei did not have an additional effect on lipid profifiles.
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Affiliation(s)
- Chien-Ying Lee
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, 40201, China.,Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan, 40201, China.,Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan, 40201, China
| | - Min-Chien Yu
- Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan, 40201, China.,Department of Integrated Chinese and Western Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, 40201, China
| | - Wu-Tsun Perng
- Department of Recreation Sport & Health Promotion, National Pingtung University of Science and Technology, Taiwan, 91201, China
| | - Chun-Che Lin
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, 40201, China.,Division of Hepatogastroenterology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, 40201, China
| | - Ming-Yung Lee
- Department of Statistics and Informatics Science, Providence University, Taiwan, 43301, China
| | - Ya-Lan Chang
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan, 40201, China.,Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan, 40201, China
| | - Ya-Yun Lai
- Department of Applied Cosmetology, National Tainan Junior College of Nursing, China, Taiwan, 700
| | - Yi-Ching Lee
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan, 40201, China.,Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan, 40201, China
| | - Yu-Hsiang Kuan
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan, 40201, China.,Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan, 40201, China
| | - James Cheng-Chung Wei
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, 40201, China.,Department of Internal Medicine, Chung Shan Medical University Hospital; Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan, 40201, China
| | - Hung-Che Shih
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, 40201, China. .,Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan, 40201, China. .,Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan, 40201, China.
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12
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Optimization of supercritical CO 2 extraction of fenugreek seed ( Trigonella foenum-graecum L.) and calculating of extracts solubility. J Supercrit Fluids 2016. [DOI: 10.1016/j.supflu.2016.07.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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13
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Molecular Imaging of Vulnerable Atherosclerotic Plaques in Animal Models. Int J Mol Sci 2016; 17:ijms17091511. [PMID: 27618031 PMCID: PMC5037788 DOI: 10.3390/ijms17091511] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 08/24/2016] [Accepted: 08/31/2016] [Indexed: 12/13/2022] Open
Abstract
Atherosclerosis is characterized by intimal plaques of the arterial vessels that develop slowly and, in some cases, may undergo spontaneous rupture with subsequent heart attack or stroke. Currently, noninvasive diagnostic tools are inadequate to screen atherosclerotic lesions at high risk of acute complications. Therefore, the attention of the scientific community has been focused on the use of molecular imaging for identifying vulnerable plaques. Genetically engineered murine models such as ApoE−/− and ApoE−/−Fbn1C1039G+/− mice have been shown to be useful for testing new probes targeting biomarkers of relevant molecular processes for the characterization of vulnerable plaques, such as vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, intercellular adhesion molecule (ICAM)-1, P-selectin, and integrins, and for the potential development of translational tools to identify high-risk patients who could benefit from early therapeutic interventions. This review summarizes the main animal models of vulnerable plaques, with an emphasis on genetically altered mice, and the state-of-the-art preclinical molecular imaging strategies.
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Abstract
Atherosclerosis is a chronic inflammatory disease affecting large and medium arteries and is considered to be a major underlying cause of cardiovascular disease (CVD). Although the development of pharmacotherapies to treat CVD has contributed to a decline in cardiac mortality in the past few decades, CVD is estimated to be the cause of one-third of deaths globally. Nutraceuticals are natural nutritional compounds that are beneficial for the prevention or treatment of disease and, therefore, are a possible therapeutic avenue for the treatment of atherosclerosis. The purpose of this Review is to highlight potential nutraceuticals for use as antiatherogenic therapies with evidence from in vitro and in vivo studies. Furthermore, the current evidence from observational and randomized clinical studies into the role of nutraceuticals in preventing atherosclerosis in humans will also be discussed.
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Affiliation(s)
- Joe W E Moss
- Cardiff School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff CF10 3AX, UK
| | - Dipak P Ramji
- Cardiff School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff CF10 3AX, UK
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15
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Zheng W, Huang R, Jiang B, Zhao Y, Zhang W, Jiang X. An Early-Stage Atherosclerosis Research Model Based on Microfluidics. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2016; 12:2022-2034. [PMID: 26890624 DOI: 10.1002/smll.201503241] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Revised: 01/25/2016] [Indexed: 06/05/2023]
Abstract
The arterial microenvironment plays a vital role in the pathology of atherosclerosis (AS). However, the interplay between the arterial microenvironment and atherogenesis remains unclear, partially due to the gap between cell culture and animal experiments. Addressing this problem, the present study reports a microfluidic AS model reconstituting early-stage AS. Physiological or AS-prone hemodynamic conditions are recapitulated on the model. The on-chip model recaptures the atherogenic responses of endothelial cells (ECs) in ways that the Petri dish could not. Significant cytotoxicity of a clinical anti-atherosclerotic drug probucol is discovered on the model, which does not appear on Petri dish but is supported by previous clinical evidence. Moreover, the anti-AS efficiency of platinum-nanoparticles (Pt-NPs) on the model shows excellent consistency with animal experiments. The early-stage AS model shows an excellent connection between Petri dish and animal experiments and highlights its promising role in bridging fundamental AS research, drug screening, and clinical trials.
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Affiliation(s)
- Wenfu Zheng
- Beijing Engineering Research Center for BioNanotechnology, CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for NanoScience and Technology, No.11 BeiYiTiao, ZhongGuanCun, Beijing, 100190, P. R. China
| | - Rong Huang
- College of Physics and Collaborative Innovation Center for Marine Biomass Fibers, Materials and Textiles of Shandong Province, Qingdao University, No. 308 Ningxia Road, Qingdao, 266071, China
| | - Bo Jiang
- Beijing Engineering Research Center for BioNanotechnology, CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for NanoScience and Technology, No.11 BeiYiTiao, ZhongGuanCun, Beijing, 100190, P. R. China
| | - Yuyun Zhao
- Beijing Engineering Research Center for BioNanotechnology, CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for NanoScience and Technology, No.11 BeiYiTiao, ZhongGuanCun, Beijing, 100190, P. R. China
| | - Wei Zhang
- Beijing Engineering Research Center for BioNanotechnology, CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for NanoScience and Technology, No.11 BeiYiTiao, ZhongGuanCun, Beijing, 100190, P. R. China
| | - Xingyu Jiang
- Beijing Engineering Research Center for BioNanotechnology, CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for NanoScience and Technology, No.11 BeiYiTiao, ZhongGuanCun, Beijing, 100190, P. R. China
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16
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Moghadasian MH, Tan Z, Le K, Shahidi F. Anti-atherogenic effects of phytosteryl oleates in apo-E deficient mice. J Funct Foods 2016. [DOI: 10.1016/j.jff.2015.11.031] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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17
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Abstract
PURPOSE OF REVIEW Probucol is a potent antioxidative drug that has been used for prevention and treatment of atherosclerotic cardiovascular diseases and xanthoma. Probucol has been used as a lipid-lowering drug for a long time especially in Japan, although Western countries quitted its use because of the reduction in serum HDL-cholesterol (HDL-C). This review highlights both basic and clinical studies that provide new insights into the pleiotropic effects of probucol. RECENT FINDINGS Recently, the mechanisms for the pharmacologic actions of probucol have been elucidated at the molecular level with a special focus on HDL metabolism and its functions. Probucol enhances plasma cholesteryl ester transfer protein activity and hepatic scavenger receptor class B type I, causing a decrease in HDL-C. It also accelerates the antioxidative function of HDL via increase in paraoxonase 1 activity. Recent retrospective analyses of probucol-treated patients with heterozygous familial hypercholesterolemia and those after coronary revascularization demonstrated a strong beneficial effect of probucol on secondary prevention of cardiovascular events and mortality. SUMMARY Probucol has pleiotropic and beneficial therapeutic effects on cardiovascular system. Although statins are effective for lowering LDL-cholesterol (LDL-C) and reducing coronary heart disease risk, probucol should be considered as an option in case statins are not effective.
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Affiliation(s)
- Shizuya Yamashita
- aDepartment of Community Medicine bDepartment of Cardiovascular Medicine, Osaka University Graduate School of Medicine cSumitomo Hospital, Osaka, Japan
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Flaxseed Oil Containing α -Linolenic Acid Ester of Plant Sterol Improved Atherosclerosis in ApoE Deficient Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:958217. [PMID: 26180602 PMCID: PMC4477243 DOI: 10.1155/2015/958217] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Accepted: 01/05/2015] [Indexed: 01/04/2023]
Abstract
Plant sterols (PS) have potential preventive function in atherosclerosis due to their cholesterol-lowering ability. Dietary α-linolenic acid in flaxseed oil is associated with a reduction in cardiovascular events through its hypolipidemic and anti-inflammation properties. This study was designed to evaluate the effects of flaxseed oil containing α-linolenic acid ester of PS (ALA-PS) on atherosclerosis and investigate the underlying mechanisms. C57BL/6 mice were administered a regular diet and apoE knockout (apoE-KO) mice were given a high fat diet alone or supplemented with 5% flaxseed oil with or without 3.3% ALA-PS for 18 weeks. Results demonstrated that flaxseed oil containing ALA-PS was synergistically interaction in ameliorating atherosclerosis as well as optimizing overall lipid levels, inhibiting inflammation and reducing oxidative stress. These data were associated with the modification effects on expression levels of genes involved in lipid metabolism (PPARα, HMGCR, and SREBPs), inflammation (IL-6, TNF, MCP-1, and VCAM-1), and oxidative stress (NADPH oxidase).
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19
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Zhu Y, Soroka D, Sang S. Oxyphytosterols as active ingredients in wheat bran suppress human colon cancer cell growth: identification, chemical synthesis, and biological evaluation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2015; 63:2264-2276. [PMID: 25658220 DOI: 10.1021/jf506361r] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Consumption of whole grains has been reported to be associated with a lower risk of colorectal cancer. Recent studies illustrated that phytochemicals in wheat bran (WB) may protect against colorectal cancer. There is a growing interest in the phytosterol contents of foods as either intrinsic or added components due to their beneficial health effects. However, little is known whether phytosterols in WB contribute the observed chemopreventative activity of the grain. In the present study, we directly purified and identified four oxyphytosterols 1-4 from sterol-enriched fraction of WB, and also successfully synthesized five sterol oxides 5-8 and 13. Using these nine compounds as references, we outlined a comprehensive profile of steroids in WB using tandem liquid chromatography mass spectrometry with electrospray ionization (LC-ESI/MS(n), n = 2-3) techniques for the first time. Among them, three sterol oxides 13, 14, and 18 are novel compounds, and 14 compounds 3, 4, 6-11, 13, 14, 16, and 18-20 were reported in WB for the first time. Our results on the inhibitory effects of available sterol oxides 1-8 and 13 against the growth of human colon cancer cells HCT-116 and HT-29 showed that compounds 2-8 exerted significant antiproliferative effects, with oxysterol 8 being the most active one in both cells. We further demonstrated that four most active sterol oxides 5-8 could induce cell death through the apoptosis pathway. Our results showed that phytosterols, particularly oxyphytosterols, in WB possess significant antiproliferative properties, and thereby may greatly contribute the observed chemoprevention of the whole grain wheat.
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Affiliation(s)
- Yingdong Zhu
- Center for Excellence in Post-Harvest Technologies, North Carolina Research Campus, North Carolina Agricultural and Technical State University , 500 Laureate Way, Kannapolis, North Carolina 28081, United States
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Flaxseed oil containing flaxseed oil ester of plant sterol attenuates high-fat diet-induced hepatic steatosis in apolipoprotein-E knockout mice. J Funct Foods 2015. [DOI: 10.1016/j.jff.2014.12.046] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Kapourchali FR, Surendiran G, Chen L, Uitz E, Bahadori B, Moghadasian MH. Animal models of atherosclerosis. World J Clin Cases 2014; 2:126-132. [PMID: 24868511 PMCID: PMC4023305 DOI: 10.12998/wjcc.v2.i5.126] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2013] [Revised: 03/15/2014] [Accepted: 04/19/2014] [Indexed: 02/05/2023] Open
Abstract
In this mini-review several commonly used animal models of atherosclerosis have been discussed. Among them, emphasis has been made on mice, rabbits, pigs and non-human primates. Although these animal models have played a significant role in our understanding of induction of atherosclerotic lesions, we still lack a reliable animal model for regression of the disease. Researchers have reported several genetically modified and transgenic animal models that replicate human atherosclerosis, however each of current animal models have some limitations. Among these animal models, the apolipoprotein (apo) E-knockout (KO) mice have been used extensively because they develop spontaneous atherosclerosis. Furthermore, atherosclerotic lesions developed in this model depending on experimental design may resemble humans’ stable and unstable atherosclerotic lesions. This mouse model of hypercholesterolemia and atherosclerosis has been also used to investigate the impact of oxidative stress and inflammation on atherogenesis. Low density lipoprotein (LDL)-r-KO mice are a model of human familial hypercholesterolemia. However, unlike apo E-KO mice, the LDL-r-KO mice do not develop spontaneous atherosclerosis. Both apo E-KO and LDL-r-KO mice have been employed to generate other relevant mouse models of cardiovascular disease through breeding strategies. In addition to mice, rabbits have been used extensively particularly to understand the mechanisms of cholesterol-induced atherosclerosis. The present review paper details the characteristics of animal models that are used in atherosclerosis research.
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Keyamura Y, Nagano C, Kohashi M, Niimi M, Nozako M, Koyama T, Yasufuku R, Imaizumi A, Itabe H, Yoshikawa T. Add-on effect of probucol in atherosclerotic, cholesterol-fed rabbits treated with atorvastatin. PLoS One 2014; 9:e96929. [PMID: 24810608 PMCID: PMC4014602 DOI: 10.1371/journal.pone.0096929] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 04/13/2014] [Indexed: 01/14/2023] Open
Abstract
Objective Lowering the blood concentration of low-density lipoprotein (LDL) cholesterol is the primary strategy employed in treating atherosclerotic disorders; however, most commonly prescribed statins prevent cardiovascular events in just 30% to 40% of treated patients. Therefore, additional treatment is required for patients in whom statins have been ineffective. In this study of atherosclerosis in rabbits, we examined the effect of probucol, a lipid-lowering drug with potent antioxidative effects, added to treatment with atorvastatin. Methods and Results Atherosclerosis was induced by feeding rabbits chow containing 0.5% cholesterol for 8 weeks. Probucol 0.1%, atorvastatin 0.001%, and atorvastatin 0.003% were administered solely or in combination for 6 weeks, beginning 2 weeks after the start of atherosclerosis induction. Atorvastatin decreased the plasma concentration of non-high-density lipoprotein cholesterol (non-HDLC) dose-dependently; atorvastatin 0.003% decreased the plasma concentration of non-HDLC by 25% and the area of atherosclerotic lesions by 21%. Probucol decreased the plasma concentration of non-HDLC to the same extent as atorvastatin (i.e., by 22%) and the area of atherosclerotic lesions by 41%. Probucol with 0.003% atorvastatin decreased the plasma concentration of non-HDLC by 38% and the area of atherosclerotic lesions by 61%. Co-administration of probucol with atorvastatin did not affect the antioxidative effects of probucol, which were not evident on treatment with atorvastatin alone, such as prevention of in vitro LDL-oxidation, increase in paraoxonase-1 activity of HDL, and decreases in plasma and plaque levels of oxidized-LDL in vivo. Conclusions Probucol has significant add-on anti-atherosclerotic effects when combined with atorvastatin treatment; suggesting that this combination might be beneficial for treatment of atherosclerosis.
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Affiliation(s)
- Yuka Keyamura
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
- Division of Biological Chemistry, Department of Molecular Biology, Showa University School of Pharmacy, Tokyo, Japan
| | - Chifumi Nagano
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Masayuki Kohashi
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Manabu Niimi
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Masanori Nozako
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Takashi Koyama
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Reiko Yasufuku
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Ayako Imaizumi
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Hiroyuki Itabe
- Division of Biological Chemistry, Department of Molecular Biology, Showa University School of Pharmacy, Tokyo, Japan
| | - Tomohiro Yoshikawa
- Free Radical Research Project, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
- * E-mail:
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Dietary phytosterol does not accumulate in the arterial wall and prevents atherosclerosis of LDLr-KO mice. Atherosclerosis 2013; 231:442-7. [PMID: 24267264 DOI: 10.1016/j.atherosclerosis.2013.10.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Revised: 10/03/2013] [Accepted: 10/16/2013] [Indexed: 12/16/2022]
Abstract
SCOPE There have been conflicting reports on the usefulness of phytosterols (PS) in preventing atherosclerosis. We evaluated the effects of dietary PS supplementation in LDLr-KO male mice on the plasma and aorta sterol concentrations and on atherosclerotic lesion development. METHODS AND RESULTS Mice were fed a high fat diet (40% of energy) supplemented with or without PS (2% w/w, n = 10). Plasma and arterial wall cholesterol and PS concentrations, lesion area, macrophage infiltration, and mRNA expression from LOX-1, CD36, ABCA1 and ABCG1 in peritoneal macrophages were measured. After 16 weeks, the plasma cholesterol concentration in PS mice was lower than that in the controls (p = 0.02) and in the arterial wall (p = 0.03). Plasma PS concentrations were higher in PS-fed animals than in controls (p < 0.0001); however, the arterial wall PS concentration did not differ between groups. The atherosclerotic lesion area in the PS group (n = 5) was smaller than that in controls (p = 0.0062) and the macrophage area (p = 0.0007). PS correlates negatively with arterial lipid content and macrophage (r = -0.76; p < 0.05). PS supplementation induced lower ABCG1 mRNA expression (p < 0.05). CONCLUSIONS Despite inducing an increase in PS plasma concentration, PS supplementation is not associated with its accumulation in the arterial wall and prevents atherosclerotic lesion development.
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Cleverley K, Du X, Premecz S, Le K, Zeglinski M, Nicholson T, Goh CY, Lu Y, Anderson HD, Moghadasian MH, Jassal DS. The effects of fish oil consumption on cardiovascular remodeling in ApoE deficient mice. Can J Physiol Pharmacol 2013; 91:960-5. [PMID: 24117264 DOI: 10.1139/cjpp-2013-0077] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Owing to their spontaneous development of atherosclerosis, apolipoprotein E knockout mice (ApoE(KO)) are one of the best studied animal models for this disease. Little is known about the utility of various omega-3 fatty acid regimens, in particular fish oils, in preventing cardiac disease in ApoE(KO) mice. The purpose of this study was to determine the cardiovascular effects of omega-3 fatty acid supplementation with either safflower oil (control), fish oil, flaxseed oil, or designed oil in ApoE(KO) mice fed a high-fat diet for a total of 16 weeks. In-vivo cardiac function was assessed weekly using murine echocardiography. Blood pressure, plasma lipid levels, and brain natriuretic peptide (BNP) were serially measured. The results show that ApoE(KO) mice fed fish oil demonstrated an increase in left ventricular wall thickness as a result of increased afterload. Despite chronic treatment with fish oil over 16 weeks, blood pressure increased in ApoE(KO) mice by 20% compared with the baseline. Both echocardiographic evidence of left ventricular hypertrophy and biochemical increase in BNP levels confirmed diastolic dysfunction in ApoE(KO) mice fed fish oil. This suggests that high-fat diet supplemented with fish oil may lead to adverse cardiovascular effects in ApoE deficient mice.
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Affiliation(s)
- Kelby Cleverley
- a Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada
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Tranfield EM, Walker DC. The ultrastructure of animal atherosclerosis: What has been done, and the electron microscopy advancements that could help scientists answer new biological questions. Micron 2013; 46:1-11. [DOI: 10.1016/j.micron.2012.12.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Accepted: 12/01/2012] [Indexed: 12/20/2022]
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Abstract
PURPOSE OF REVIEW Plant sterols as ingredients to functional foods are recommended for lowering LDL cholesterol. However, there is an ongoing discussion whether the use of plant sterols is safe. RECENT FINDINGS Genetic analyses showed that common variants of the ATP binding cassette transporter G8 (ABCG8) and ABO genes are associated with elevated circulating plant sterols and higher risk for cardiovascular disease. However, these data do not prove a causal role for plant sterols in atherosclerosis because the risk alleles in ABCG8 and ABO are also related to elevated total and LDL cholesterol levels. The ABO locus exhibits still further pleiotropy. Moreover, analyses in the general population indicated that moderately elevated circulating plant sterols are not correlated with present or future vascular disease. In agreement, novel studies using food frequency questionnaires, studies in experimental animals, and dietary intervention studies support that ingestion of plant sterols may be beneficial to cardiovascular health. SUMMARY Taken together, current evidence supports the recommendations for the use of plant sterols as LDL cholesterol-lowering agents. Nevertheless, a prospective, randomized, controlled, double-blinded, intervention trial conclusively showing that plant sterol supplementation will prevent hard cardiovascular endpoints is not available to date.
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Affiliation(s)
- Günther Silbernagel
- Division of Endocrinology, Diabetology, Nephrology, Vascular Disease, and Clinical Chemistry, Department of Internal Medicine, Eberhard-Karls-University Tübingen, Tübingen, Germany.
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Progress and prospective of plant sterol and plant stanol research: Report of the Maastricht meeting. Atherosclerosis 2012; 225:521-33. [DOI: 10.1016/j.atherosclerosis.2012.09.018] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Accepted: 09/16/2012] [Indexed: 12/29/2022]
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Cicero AFG, Ferroni A, Ertek S. Tolerability and safety of commonly used dietary supplements and nutraceuticals with lipid-lowering effects. Expert Opin Drug Saf 2012; 11:753-66. [DOI: 10.1517/14740338.2012.705827] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Tan Z, Le K, Moghadasian M, Shahidi F. Enzymatic synthesis of phytosteryl docosahexaneates and evaluation of their anti-atherogenic effects in apo-E deficient mice. Food Chem 2012; 134:2097-104. [PMID: 23442661 DOI: 10.1016/j.foodchem.2012.04.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2011] [Revised: 03/15/2012] [Accepted: 04/03/2012] [Indexed: 12/14/2022]
Abstract
Phytosterols have attracted much attention in recent years due to their health benefits, such as cholesterol lowering, anti-inflammatory, anti-atherogenicity, and anti-cancer potential. Docosahexaenoic acid (DHA) has been demonstrated to possess cardioprotective and immune-enhancing effects. Esterification of phytosterols with DHA may render improved physiochemical properties such as solubility, miscibility, oxidative stability and hence bioactivity and bioavailability. Thus, phytosteryl docosahexaneates (PS-DHA) may offer both the benefits of phytosterols and DHA, possibly in a synergistic manner. Here, we describe a method for enzymatic synthesis of phytosteryl docosahexaneates and evaluation of metabolic and cardiovascular benefits in apo-E deficient (apo E-KO) mice. The structures of phytosteryl docosahexaneates were confirmed by infrared (IR) and high performance liquid chromatography-mass spectrometry (HPLC-MS) using both normal and reverse phase chromatography. Apo E-KO mice were fed with an atherogenic diet containing 2% (w/w) PS-DHA for 7 weeks. Plasma lipid levels and the extent and complexity of atherosclerotic lesions were examined and compared with those in the control group. The PS-DHA-treated mice had significantly lower plasma cholesterol levels and three times smaller atherosclerotic lesions in the aortic roots. This pilot study suggests cardiovascular benefits for PS-DHA. Further experimental and clinical studies are needed to confirm such benefits of PS-DHA.
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Affiliation(s)
- Zhuliang Tan
- Department of Biochemistry, Memorial University of Newfoundland, St John's, NL, Canada A1B 3X9
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Lottenberg AM, Bombo RP, Ilha A, Nunes VS, Nakandakare ER, Quintão EC. Do clinical and experimental investigations support an antiatherogenic role for dietary phytosterols/stanols? IUBMB Life 2012; 64:296-306. [DOI: 10.1002/iub.1006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2011] [Accepted: 12/31/2011] [Indexed: 11/12/2022]
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Torrelo G, Torres CF, Reglero G. Enzymatic strategies for solvent-free production of short and medium chain phytosteryl esters. EUR J LIPID SCI TECH 2012. [DOI: 10.1002/ejlt.201100346] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Párraga I, López-Torres J, Andrés F, Navarro B, del Campo JM, García-Reyes M, Galdón MP, Lloret Á, Precioso JC, Rabanales J. Effect of plant sterols on the lipid profile of patients with hypercholesterolaemia. Randomised, experimental study. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2011; 11:73. [PMID: 21910898 PMCID: PMC3180270 DOI: 10.1186/1472-6882-11-73] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Accepted: 09/12/2011] [Indexed: 11/23/2022]
Abstract
BACKGROUND Studies have been conducted on supplementing the daily diet with plant sterol ester-enriched milk derivatives in order to reduce LDL-cholesterol levels and, consequently, cardiovascular risk. However, clinical practice guidelines on hypercholesterolaemia state that there is not sufficient evidence to recommend their use in subjects with hypercholesterolaemia. The main objective of this study is to determine the efficacy of the intake of 2 g of plant sterol esters a day in lowering LDL-cholesterol levels in patients diagnosed with hypercholesterolaemia. The specific objectives are: 1) to quantify the efficacy of the daily intake of plant sterol esters in lowering LDL-cholesterol, total cholesterol and cardiovascular risk in patients with hypercholesterolaemia; 2) to evaluate the occurrence of adverse effects of the daily intake of plant sterol esters; 3) to identify the factors that determine a greater reduction in lipid levels in subjects receiving plant sterol ester supplements. METHODS/DESIGN Randomised, double-blind, placebo controlled experimental trial carried out at family doctors' surgeries at three health centres in the Health Area of Albacete (Spain). The study subjects will be adults diagnosed with "limit" or "defined" hypercholesterolaemia and who have LDL cholesterol levels of 130 mg/dl or over. A dairy product in the form of liquid yoghurt containing 2 g of plant sterol ester per container will be administered daily after the main meal, for a period of 24 months. The control group will receive a daily unit of yogurt not supplemented with plant sterol esters that has a similar appearance to the enriched yoghurt. The primary variable is the change in lipid profile at 1, 3, 6, 12, 18 and 24 months. The secondary variables are: change in cardiovascular risk, adherence to the dairy product, adverse effects, adherence to dietary recommendations, frequency of food consumption, basic physical examination data, health problems, lipid-lowering medication, physical activity, smoking habits and socio-demographic variables. DISCUSSION If plant sterol ester supplements were effective a sounder recommendation for the consumption of plant sterols in subjects with hypercholesterolaemia could be made.
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Affiliation(s)
- Ignacio Párraga
- Research Unit, Primary Care Head Office of Albacete, Health Care Service of Castilla-La Mancha, Marqués de Villores 6-8, 02001 Albacete, Spain
| | - Jesús López-Torres
- Research Unit, Primary Care Head Office of Albacete, Health Care Service of Castilla-La Mancha, Marqués de Villores 6-8, 02001 Albacete, Spain
| | - Fernando Andrés
- Research Unit, Primary Care Head Office of Albacete, Health Care Service of Castilla-La Mancha, Marqués de Villores 6-8, 02001 Albacete, Spain
| | - Beatriz Navarro
- Research Unit, Primary Care Head Office of Albacete, Health Care Service of Castilla-La Mancha, Marqués de Villores 6-8, 02001 Albacete, Spain
| | - José M del Campo
- Almansa Health Centre, Health Care Service of Castilla-La Mancha, C/San Juan s/n, 02640 Almansa, Albacete, Spain
| | - Mercedes García-Reyes
- Albacete Area III Health Centre, Health Care Service of Castilla-La Mancha, Plaza La Mancha s/n, 02001 Albacete, Spain
| | - María P Galdón
- La Roda Health Centre, Health Care Service of Castilla-La Mancha, C/Martínez 63, 02630 La Roda, Albacete, Spain
| | - Ángeles Lloret
- Pharmacy Service, Primary Care Head Office of Albacete, Health Care Service of Castilla-La Mancha, Marqués de Villores 6-8, 02001 Albacete, Spain
| | - Juan C Precioso
- La Roda Health Centre, Health Care Service of Castilla-La Mancha, C/Martínez 63, 02630 La Roda, Albacete, Spain
| | - Joseba Rabanales
- Research Unit, Primary Care Head Office of Albacete, Health Care Service of Castilla-La Mancha, Marqués de Villores 6-8, 02001 Albacete, Spain
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Othman RA, Moghadasian MH. Beyond cholesterol-lowering effects of plant sterols: clinical and experimental evidence of anti-inflammatory properties. Nutr Rev 2011; 69:371-82. [PMID: 21729090 DOI: 10.1111/j.1753-4887.2011.00399.x] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Inflammation is a strong risk factor for cardiovascular disease. Dietary plant sterols are known to reduce plasma cholesterol levels and thereby reduce cardiovascular risk. Recent observations from animal and human studies have demonstrated anti-inflammatory effects of phytosterols. For example, several animal and human studies report reductions in the levels of proinflammatory cytokines, including C-reactive protein, after consumption of dietary plant sterols. Although the cholesterol-lowering effects of phytosterols in humans are well documented, studies on the effects of phytosterols on inflammatory markers have produced inconsistent results. This review summarizes and discusses findings from recent animal and human studies with regard to the potential anti-inflammatory effects of dietary phytosterols. Findings on the effects of plant sterols on inflammation remain limited and confounding. Future research using better-designed and well-controlled laboratory studies and clinical trials are needed to fully understand the mechanisms through which phytosterols influence inflammation. Additional well-designed placebo-controlled studies are needed to better understand how and to what extent dietary plant sterols may modify the immune system and the production of inflammatory markers.
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Affiliation(s)
- Rgia A Othman
- Department of Human Nutritional Sciences, University of Manitoba and Canadian Centre for Agri-food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Canada
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Perona JS, Fitó M, Covas MI, Garcia M, Ruiz-Gutierrez V. Olive oil phenols modulate the triacylglycerol molecular species of human very low-density lipoprotein. A randomized, crossover, controlled trial. Metabolism 2011; 60:893-9. [PMID: 20934731 DOI: 10.1016/j.metabol.2010.08.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2010] [Revised: 08/20/2010] [Accepted: 08/23/2010] [Indexed: 01/29/2023]
Abstract
Virgin olive oil phenolic compounds have been revealed to be potent antioxidants as part of the Mediterranean diet. To test the hypothesis that these phenolics can modulate the serum and very low-density lipoprotein (VLDL) triacylglycerol concentrations in humans, a double-blind, randomized, crossover trial was designed. Thirty-three participants received 25 mL/d of refined olive oil (devoid of phenolic content [PC]), common olive oil (PC = 370 mmol/kg), and virgin olive oil (PC = 825 mmol/kg) in a Latin square design. The 3 olive oils were administered over 3 periods of 3 weeks, each one preceded by 2-week washout periods. All analyses were carried out on an intention-to-treat basis. The interventions did not modify the concentrations of serum and low-density lipoprotein cholesterol and triacylglycerol; but they exerted changes in the cholesterol, triacylglycerol, and phospholipid content of VLDL. The virgin olive oil consumption led to increased oleic and palmitic acids, as well as decreased linoleic acid, in VLDL. The main outcome was the significant dose-dependent linear trend between the PC in the olive oils and the palmitic (16:0) and linoleic (18:2 n-6) acid and their corresponding triacylglycerol molecular species in VLDL.
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Affiliation(s)
- Javier S Perona
- Group of Nutrition and Lipid Metabolism, Instituto de la Grasa (CSIC), Av. Padre García Tejero, 4, 41012 Seville, Spain.
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Bouguerne B, Belkheiri N, Bedos-Belval F, Vindis C, Uchida K, Duran H, Grazide MH, Baltas M, Salvayre R, Nègre-Salvayre A. Antiatherogenic effect of bisvanillyl-hydralazone, a new hydralazine derivative with antioxidant, carbonyl scavenger, and antiapoptotic properties. Antioxid Redox Signal 2011; 14:2093-106. [PMID: 21043830 DOI: 10.1089/ars.2010.3321] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Reactive oxygen species (ROS) generated within the vascular wall trigger low-density lipoprotein (LDL) oxidation, lipid peroxidation, and carbonyl stress that are involved in atherogenesis. We recently reported that the antihypertensive drug, hydralazine, exhibits carbonyl scavenger and antiatherogenic properties, but only moderate antioxidant activity, so that high concentrations are required for inhibiting LDL oxidation. We aimed to develop agents sharing both antioxidant and carbonyl scavenger properties. We have synthesized a new hydralazine derivative, the bisvanillyl-hydralazone (BVH). BVH strongly inhibited LDL oxidation induced by copper and by human endothelial cells (HMEC-1), and prevented the formation of macrophagic foam cells. BVH reduced both the extracellular generation of ROS (superoxide anion and hydrogen peroxide) induced by oxidized LDL (oxLDL), as well as intracellular oxidative stress and proteasome activation, NFkappaB activation, and oxLDL-mediated proinflammatory signaling. In parallel, BVH prevented the carbonyl stress induced by oxLDL on cellular proteins, and blocked the apoptotic cascade as assessed by the inhibition of Bid cleavage, cytochrome C release, and DEVDase activation. Lastly, BVH prevented atherogenesis and carbonyl stress in apoE(-/-) mice. In conclusion, BVH is the prototype of a new class of antioxidant and carbonyl scavenger agents designed for new therapeutical approaches in atherosclerosis.
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Ahmadie R, Santiago JJ, Walker J, Fang T, Le K, Zhao Z, Azordegan N, Bage S, Lytwyn M, Rattan S, Dixon IMC, Kardami E, Moghadasian MH, Jassal DS. A high-lipid diet potentiates left ventricular dysfunction in nitric oxide synthase 3-deficient mice after chronic pressure overload. J Nutr 2010; 140:1438-44. [PMID: 20554900 DOI: 10.3945/jn.110.123091] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
A high-lipid diet (HLD) may lead to adverse left ventricular (LV) remodeling and endothelial dysfunction in conditions of hemodynamic stress. Although congenital absence of nitric oxide synthase 3 (NOS3) leads to adverse LV remodeling after transverse aortic constriction (TAC), the effects of a HLD in this state remains unknown. Wild-type (WT) and NOS3 knockout mice (NOS3(-/-)) were randomized into the following 4 groups: 1) WT + low-lipid diet (LLD) (10% of energy); 2) WT + HLD (60% of energy); 3) NOS3(-/-) + LLD; and 4) NOS3(-/-) + HLD for a total of 12 wk. After 1 wk of randomization, TAC was performed on all groups. Serial echocardiography revealed a decrease in LV ejection fraction (LVEF) in WT and NOS3(-/-) mice fed the HLD compared with those fed the LLD diet at 12 wk post-TAC. Mice fed the NOS3(-/-) + HLD diet had a lower LVEF compared with mice in the other 3 groups (P < 0.05). There was greater myocyte hypertrophy, interstitial fibrosis, and percentage change in plasma cholesterol concentrations in the NOS3(-/-) + HLD group 12 wk post-TAC compared with the other 3 groups. Although high molecular weight fibroblast growth factor-2, a marker of cardiac hypertrophy, was more upregulated in the NOS3(-/-) + HLD group than in the other groups, markers of the renin-angiotensin system did not differ among them. A HLD potentiates LV dysfunction in NOS3(-/-) mice in a chronic pressure overload state.
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Affiliation(s)
- Roien Ahmadie
- Institute of Cardiovascular Sciences, St. Boniface General Hospital, University of Manitoba, Winnipeg, Manitoba, Canada
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Hansel B, Courie R, Bayet Y, Delestre F, Bruckert E. [Phytosterols and atherosclerosis]. Rev Med Interne 2010; 32:124-9. [PMID: 20650550 DOI: 10.1016/j.revmed.2010.06.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2010] [Revised: 04/19/2010] [Accepted: 06/07/2010] [Indexed: 10/19/2022]
Abstract
Phytosterols/stanols (PS) enriched food products have been shown to consistently lower plasma cholesterol levels. The intake of 2g/d of PS decreases LDL-cholesterol by about 10%. With respect to the association of LDL-cholesterol lowering with reduction in the cardiovascular (CV) risk, it is likely that supplementation in PS reduces the incidence of CV disease. In addition, the vast majority of animal studies have shown that oral administration of PS reduces the progression atherosclerosis. However, it has been recently suggested that an increase in PS plasma concentrations may increase CV risk. Evidence to support this hypothesis come mainly from observations in sitosterolemic patients who hyperabsorb PS and cholesterol and display very high levels of PS, which may be associated with a premature atherosclerosis. Some epidemiological studies in non-sitosterolemic subjects have shown a positive correlation between PS plasma levels and coronary heart disease. However, these are observational studies and some of them present major methodological bias. In addition, recent studies with a larger number of subjects have indicated, either an absence or a negative relationship between PS and the incidence of CV disease. The guidelines of several French and international institutions recommend the use of PS enriched food in association with other classical recommendations in hypercholesterolemic subjects. However, further studies are highly encouraged to examine the CV benefit of PS enriched food.
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Affiliation(s)
- B Hansel
- Service d'endocrinologie et de prévention cardiovasculaire, hôpital de la Pitié-Salpêtrière, 47-83, boulevard de l'Hôpital, 75013 Paris, France.
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Silbernagel G, Fauler G, Hoffmann MM, Lütjohann D, Winkelmann BR, Boehm BO, März W. The associations of cholesterol metabolism and plasma plant sterols with all-cause and cardiovascular mortality. J Lipid Res 2010; 51:2384-93. [PMID: 20228406 DOI: 10.1194/jlr.p002899] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Moderately elevated levels of plasma plant sterols have been suspected to be causally involved in atherosclerosis. The aim of this study was to investigate whether plant sterols and other markers of sterol metabolism predicted all-cause and cardiovascular mortality in participants of the Ludwigshafen Risk and Cardiovascular health (LURIC) study. A total of 1,257 individuals who did not use statins and at baseline had a mean (+/- SD) age of 62.8 (+/- 11.0) years were included in the present analysis. Lathosterol, cholestanol, campesterol, and sitosterol were measured to estimate cholesterol synthesis and absorption. The mean (+/- SD) time of the follow-up for all-cause and cardiovascular mortality was 7.32 (+/- 2.3) years. All-cause (P = 0.001) and cardiovascular (P = 0.006) mortality were decreased in the highest versus the lowest lathosterol to cholesterol tertile. In contrast, subjects in the third cholestanol to cholesterol tertile had increased all-cause (P < 0.001) and cardiovascular mortality (P = 0.010) compared with individuals in the first tertile. The third campesterol to cholesterol tertile was associated with increased all-cause mortality (P = 0.025). Sitosterol to cholesterol tertiles were not significantly related to all-cause or cardiovascular mortality. The data suggest that high absorption and low synthesis of cholesterol predict increased all-cause and cardiovascular mortality in LURIC participants.
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Affiliation(s)
- Guenther Silbernagel
- Division of Endocrinology, Department of Internal Medicine, Eberhard-Karls-University, Tübingen, Germany
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40
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Derdemezis CS, Filippatos TD, Mikhailidis DP, Elisaf MS. Review article: effects of plant sterols and stanols beyond low-density lipoprotein cholesterol lowering. J Cardiovasc Pharmacol Ther 2010; 15:120-34. [PMID: 20200328 DOI: 10.1177/1074248409357921] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Consumption of foods and supplements enriched with plant sterols/stanols (PS) may help reduce low-density lipoprotein cholesterol (LDL-C) levels. In this review, we consider the effects of PS beyond LDL-C lowering. Plant sterols/stanols exert beneficial effects on other lipid variables, such as apolipoprotein (apo) B/apoAI ratio and, in some studies, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Plant sterols/stanols may also affect inflammatory markers, coagulation parameters, as well as platelet and endothelial function. Evidence also exists about a beneficial effect on oxidative stress, but this does not seem to be of greater degree than that expected from the LDL-C lowering. Many of these effects have been demonstrated in vitro and animal models. Some in vitro effects cannot be seen in vivo or in humans at usual doses. The epidemiological studies that evaluated the association of plasma PS concentration with cardiovascular disease (CVD) risk do not provide a definitive answer. Long-term randomized placebo-controlled studies are required to clarify the effects of supplementation with PS on CVD risk and progression of atherosclerosis.
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Affiliation(s)
- Christos S Derdemezis
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece
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41
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Increased plasma levels of plant sterols and atherosclerosis: a controversial issue. Curr Atheroscler Rep 2009; 11:391-8. [PMID: 19664384 DOI: 10.1007/s11883-009-0059-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
A number of studies have raised the possibility of circulating plant sterols being a risk factor in the pathogenesis of atherosclerosis. Evidence in support of this hypothesis comes mainly from observations in sitosterolemic patients, who hyperabsorb plant sterols and suffer premature atherosclerosis. Accordingly, the atherogenicity of plant sterols of dietary origin is currently under debate, in view of the widespread use of cholesterol-lowering functional foods enriched with these compounds. Although some reports have suggested the vascular perils of small increases in plasma plant sterol concentrations, other prospective and large population-based studies have indicated otherwise. Further, the potential risk of plant sterol-enriched foods may be counterbalanced by the notable reduction in plasma cholesterol. This review summarizes the current evidence on the possible impact of plant sterols as a risk factor for atherosclerosis.
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Xu Z, Azordegan N, Zhao Z, Le K, Othman RA, Moghadasian MH. Pro-atherogenic effects of probucol in apo E-KO mice may be mediated through alterations in immune system: Parallel alterations in gene expression in the aorta and liver. Atherosclerosis 2009; 206:427-33. [DOI: 10.1016/j.atherosclerosis.2009.03.023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2008] [Revised: 03/17/2009] [Accepted: 03/18/2009] [Indexed: 10/21/2022]
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Zhao Z, Xu Z, Le K, Azordegan N, Riediger ND, Moghadasian MH. Lack of evidence for antiatherogenic effects of wheat bran or corn bran in apolipoprotein E-knockout mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2009; 57:6455-6460. [PMID: 19601675 DOI: 10.1021/jf900090q] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Epidemiological studies have suggested that intake of whole grains is inversely associated with coronary artery disease. The mechanisms, however, are not completely clear. We tested the hypothesis that intake of wheat bran or corn bran would (1) increase the plasma concentration of phenolic antioxidants and (2) reduce atherosclerosis in apo E-knockout mice. Apo E-knockout (E-KO) mice were fed for 18 weeks with a 0.1% cholesterol-supplemented diet in the absence of grain brans or the presence of 1.7% yellow dent corn bran or 3.3% hard red spring wheat bran. The concentration of antioxidant ferulic acid in plasma and urine was measured by HPLC to monitor the bioavailability of grain phenolics. Plasma lipoprotein profiles were determined by a combination of HPLC and online enzymatic methods. Urinary 15-isoprostane F(2t), an in vivo LDL oxidation biomarker, and atherosclerotic lesions were analyzed by ELISA and histological methods, respectively. Dietary supplementation with corn or wheat bran resulted in a 4- and 24-fold increase, respectively, in urinary excretion of ferulic acid. The urinary recovery rate of ferulic acid from the two brans in apo E-KO mice was approximately 1.9-2.9%. Dietary corn bran but not wheat bran also significantly increased the concentration of total ferulic acid in plasma. Nevertheless, the supplementation with either bran product for 18 weeks did not significantly alter the urinary excretion of 15-isoprostane F(2t), change the lipoprotein profiles, nor reduce the atherosclerotic lesion development in this animal model. The results suggest that phenolic antioxidants from the two types of bran may not be sufficient to reduce atherosclerosis in this animal model.
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Affiliation(s)
- Zhaohui Zhao
- Department of Human Nutritional Sciences, University of Manitoba, and Canadian Center for Agri-food Research in Health and Medicine, St Boniface Hospital Research Center, Winnipeg, Canada
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Cytotoxic components of Pereskia bleo (Kunth) DC. (Cactaceae) leaves. Molecules 2009; 14:1713-24. [PMID: 19471192 PMCID: PMC6254274 DOI: 10.3390/molecules14051713] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2009] [Revised: 04/07/2009] [Accepted: 05/04/2009] [Indexed: 01/15/2023] Open
Abstract
Dihydroactinidiolide (1) and a mixture of sterols [campesterol (2), stigmasterol (3) and β-sitosterol (4)], together with the previously isolated individual compounds β-sitosterol (4), 2,4-di-tert-butylphenol (5), α-tocopherol (6), phytol (7) were isolated from the active ethyl acetate fraction of Pereskia bleo (Kunth) DC. (Cactaceae) leaves. Cytotoxic activities of the above mentioned compounds against five human carcinoma cell lines, namely the human nasopharyngeal epidermoid carcinoma cell line (KB), human cervical carcinoma cell line (CasKi), human colon carcinoma cell line (HCT 116), human hormone-dependent breast carcinoma cell line (MCF7) and human lung carcinoma cell line (A549); and non-cancer human fibroblast cell line (MRC-5) were investigated. Compound 5 possessed very remarkable cytotoxic activity against KB cells, with an IC50 value of 0.81µg/mL. This is the first report on the cytotoxic activities of the compounds isolated from Pereskia bleo.
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45
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Brufau G, Canela MA, Rafecas M. Phytosterols: physiologic and metabolic aspects related to cholesterol-lowering properties. Nutr Res 2009; 28:217-25. [PMID: 19083411 DOI: 10.1016/j.nutres.2008.02.003] [Citation(s) in RCA: 178] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2007] [Revised: 01/09/2008] [Accepted: 02/04/2008] [Indexed: 11/15/2022]
Abstract
The aim of this review is to give a general contemporary overview of the physiologic effects of phytosterols and their role in cholesterol uptake in the intestinal tract. The mechanism of phytosterols action is based on its ability to reduce cholesterol absorption. Doses of 0.8 to 4.0 g/d of phytosterols were used to reduce low-density lipoprotein cholesterol concentrations by 10% to 15%, although most of the studies described used 2 g/d of phytosterol to achieve a reduction of 10% in low-density lipoprotein cholesterol concentrations. Although some studies point to the possibility that elevated plasma phytosterol concentrations could contribute to the development of premature coronary artery diseases, extensive safety evaluation studies have been conducted for these compounds, and they have been considered safe.
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Affiliation(s)
- Gemma Brufau
- Department of Nutrition and Food Science, CeRTA (Nutrició i Salut), University of Barcelona, 08028 Barcelona, Spain
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46
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Abdullah MM, Riediger NN, Chen Q, Zhao Z, Azordegan N, Xu Z, Fischer G, Othman RA, Pierce GN, Tappia PS, Zou J, Moghadasian MH. Effects of long-term consumption of a high-fructose diet on conventional cardiovascular risk factors in Sprague-Dawley rats. Mol Cell Biochem 2009; 327:247-56. [DOI: 10.1007/s11010-009-0063-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2008] [Accepted: 02/05/2009] [Indexed: 01/04/2023]
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Jassal DS, Othman RA, Ahmadie R, Fang T, Zieroth S, Fischer G, Moghadasian MH. The Role of Tissue Doppler Imaging in the Noninvasive Detection of Chronic Rejection after Heterotopic Cardiac Transplantation in Rats. Echocardiography 2009; 26:37-43. [DOI: 10.1111/j.1540-8175.2008.00751.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Abstract
So far, a protective influence of phytosterols on the human organism and atherogenesis has been suggested. Most studies have concentrated on the cytotoxic efficacy of phytosterols on cancer cells. However, there are only a few reports showing their influence on normal cells. The aim of the present study was to determine whether dietary plant sterols and their thermal processing products could influence the viability of normal, abdominal endothelial cells that play a crucial role in atherogenesis. Thus, we studied the effect of rapeseed oil-extract components, β-sitosterol, cholesterol and their epoxy-derivatives, 5α,6α-epoxy-β-sitosterol and 5α,6α-epoxycholesterol, on the proliferation and viability of human abdominal aorta endothelial cells HAAE-2in vitro. We showed strong cytotoxic properties of β-sitosterol in HAAE-2 cells (half maximal inhibitory concentration (IC50) = 1·99 (sem0·56) μm) and, interestingly, a weaker cytotoxic effect of 5α,6α-epoxy-β-sitosterol (IC50>200 μm). Moreover, we observed a significantly stronger cytotoxic activity of β-sitosterol than cholesterol (IC50 = 8·99 (sem2·74) μm). We also revealed that β-sitosterol as well as cholesterol caused apoptosis, inducing caspase-3 activity in the cells (60 % increase compared with control cells) that corresponded to the DNA fragmentation analysis in a terminal uridine deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling (TUNEL) study. Although absorption of plant sterols is low compared with cholesterol, they can still influence other physiological functions. Since they effectively reduce serum LDL-cholesterol and atherosclerotic risk but also decrease the viability of cancer cells as well as normal cells in a time- and dose-dependent mannerin vitro, their influence on other metabolic processes remains to be elucidated.
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Calpe-Berdiel L, Escolà-Gil JC, Rotllan N, Blanco-Vaca F. Phytosterols do not change susceptibility to obesity, insulin resistance, and diabetes induced by a high-fat diet in mice. Metabolism 2008; 57:1497-501. [PMID: 18940385 DOI: 10.1016/j.metabol.2008.06.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2007] [Accepted: 06/30/2008] [Indexed: 10/21/2022]
Abstract
Most studies have focused on the cholesterol-lowering activity of phytosterols; however, other biological actions have also been attributed to these plant compounds. In this study, we investigated whether phytosterols could delay (progression phase) and/or reverse (regression phase) insulin resistance or type 2 diabetes mellitus in an experimental mouse model of diet-induced obesity, insulin resistance, and diabetes. Body mass, plasma lipid levels, insulin resistance, and hyperglycemia were determined. Phytosterol intake did not improve these metabolic parameters. Therefore, we were unable to substantiate any protective effect of phytosterol intake on diabetes development or regression in the mouse model used.
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Affiliation(s)
- L Calpe-Berdiel
- Institut de Recerca, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain
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50
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Silbernagel G, Fauler G, Renner W, Landl EM, Hoffmann MM, Winkelmann BR, Boehm BO, März W. The relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease. J Lipid Res 2008; 50:334-41. [PMID: 18769018 DOI: 10.1194/jlr.p800013-jlr200] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Changes in the balance of cholesterol absorption and synthesis and moderately elevated plasma plant sterols have been suggested to be atherogenic. Measuring cholestanol, lathosterol, campesterol, and sitosterol, we investigated the relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease (CAD) in 2,440 participants of the Ludwigshafen Risk and Cardiovascular health (LURIC) study. The coronary status was determined by angiography, and the severity of CAD was assessed by the Friesinger Score (FS). An increase in the ratio of cholestanol to cholesterol was associated with high FS (P = 0.006). In contrast, a high ratio of lathosterol to cholesterol went in parallel with low FS (P < 0.001). Whereas the campesterol to cholesterol ratio significantly correlated with the FS (P = 0.026), the relationship of the sitosterol to cholesterol ratio with the FS did not reach statistical significance in the whole group. Increased campesterol, sitosterol, and cholestanol to lathosterol ratios were associated high FS (P < 0.001). To conclude, there is a modest association of high cholesterol absorption and low cholesterol synthesis with an increased severity of CAD. An atherogenic role of plasma plant sterols themselves, however, seems unlikely in subjects without sitosterolaemia.
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Affiliation(s)
- Guenther Silbernagel
- Division of Endocrinology, Diabetology, Nephrology, Vascular Disease, and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany
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