• Nutrition Research and Practice
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• v.18 no.5
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• pp.617-632
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• 2024

BACKGROUND/OBJECTIVES: Atherosclerosis particularly due to high circulating level of low-density lipoprotein is a major cause of cardiovascular diseases. Ellagic acid is a natural polyphenolic compound rich in pomegranates and berries. Our previous study showed that ellagic acid improved functionality of reverse cholesterol transport in murine model of atherosclerosis. The aim of this study is to investigate whether ellagic acid inhibited inflammation-associated atherosclerotic plaque formation in cholesterol-fed apolipoprotein E (apoE)-knockout (KO) mice. MATERIALS/METHODS: Wild type mice and apoE-KO mice were fed a cholesterol-rich Paigen diet for 10 weeks to induce severe atherosclerosis. Concurrently, 10 mg/kg ellagic acid was orally administered to the apoE-KO mice. Plaque lesion formation and lipid deposition were examined by staining with hematoxylin and eosin, Sudan IV and oil red O. RESULTS: The plasma leukocyte profile of cholesterol-fed mice was not altered by apoE deficiency. Oral administration of ellagic acid attenuated plaque lesion formation and lipid deposition in the aorta tree of apoE-KO mice. Ellagic acid substantially reduced plasma levels of soluble vascular cell adhesion molecule and interferon-γ in Paigen diet-fed apoE-KO mice. When 10 mg/kg ellagic acid was administered to cholesterol-fed apoE-KO mice, the levels of CD68 and MCP-1 were strongly reduced in aorta vessels. The protein expression level of nitric oxide synthase-2 (NOS2) in the aorta was highly enhanced by supplementation of ellagic acid to apoE-KO mice, but the expression level of heme oxygenase-1 (HO-1) in the aorta was reduced. Furthermore, ellagic acid diminished the increased aorta expression of the inflammatory adhesion molecules in cholesterol-fed apoE-KO mice. The treatment of ellagic acid inhibited the scavenger receptor-B1 expression in the aorta of apoE-KO mice, while the cholesterol efflux-related transporters were not significantly changed. CONCLUSION: These results suggest that ellagic acid may be an atheroprotective compound by attenuating apoE deficiency-induced vascular inflammation and reducing atherosclerotic plaque lesion formation.

• Nutrition Research and Practice
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• v.18 no.2
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• pp.194-209
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• 2024

BACKGROUND/OBJECTIVES: High levels of plasma low-density lipoprotein (LDL) cholesterol are an important determinant of atherosclerotic lesion formation. The disruption of cholesterol efflux or reverse cholesterol transport (RCT) in peripheral tissues and macrophages may promote atherogenesis. The aim of the current study was to examine whether bioactive ellagic acid, a functional food component, improved RCT functionality and high-density lipoprotein (HDL) function in diet-induced atherogenesis of apolipoproteins E (apoE) knockout (KO) mice. MATERIALS/METHODS: Wild type mice and apoE KO mice were fed a high-cholesterol Paigen diet for 10 weeks to induce hypercholesterolemia and atherosclerosis, and concomitantly received 10 mg/kg ellagic acid via gavage. RESULTS: Supplying ellagic acid enhanced induction of apoE and ATP-binding cassette (ABC) transporter G1 in oxidized LDL-exposed macrophages, facilitating cholesterol efflux associated with RCT. Oral administration of ellagic acid to apoE KO mice fed on Paigen diet improved hypercholesterolemia with reduced atherogenic index. This compound enhanced the expression of ABC transporters in peritoneal macrophages isolated from apoE KO mice fed on Paigen diet, indicating increased cholesterol efflux. Plasma levels of cholesterol ester transport protein and phospholipid transport protein involved in RCT were elevated in mice lack of apoE gene, which was substantially reduced by supplementing ellagic acid to Paigen diet-fed mice. In addition, ellagic acid attenuated hepatic lipid accumulation in apoE KO mice, evidenced by staining of hematoxylin and eosin and oil red O. Furthermore, the supplementation of 10 mg/kg ellagic acid favorably influenced the transcriptional levels of hepatic LDL receptor and scavenger receptor-B1 in Paigen diet-fed apoE KO mice. CONCLUSION: Ellagic acid may be an athero-protective dietary compound encumbering diet-induced atherogenesis though improving the RCT functionality.

• Nutrition Research and Practice
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• v.17 no.6
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• pp.1099-1112
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• 2023

BACKGROUND/OBJECTIVES: Dyslipidemia causes metabolic disorders such as atherosclerosis and fatty liver syndrome due to abnormally high blood lipids. Purple perilla frutescens extract (PPE) possesses various bioactive compounds such as α-asarone, chlorogenic acid and rosmarinic acid. This study examined whether PPE and α-asarone improved dyslipidemia-associated inflammation and inhibited atheroma formation in apolipoprotein E (apoE)-deficient mice, an experimental animal model of atherosclerosis. MATERIALS/METHODS: ApoE-deficient mice were fed on high cholesterol-diet (Paigen's diet) and orally administrated with 10-20 mg/kg PPE and α-asarone for 10 wk. RESULTS: The Paigen's diet reduced body weight gain in apoE-deficient mice, which was not restored by PPE or α-asarone. PPE or α-asarone improved the plasma lipid profiles in Paigen's diet-fed apoE-deficient mice, and despite a small increase in high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein (LDL)-cholesterol, and very LDL were significantly reduced. Paigen's diet-induced systemic inflammation was reduced in PPE or α-asarone-treated apoE-deficient mice. Supplying PPE or α-asarone to mice lacking apoE suppressed aorta atherogenesis induced by atherogenic diet. PPE or α-asarone diminished aorta accumulation of CD68- and/or F4/80-positive macrophages induced by atherogenic diet in apoE-deficient mice. Treatment of apoE-deficient mice with PPE and α-asarone resulted in a significant decrease in plasma cholesteryl ester transfer protein level and an increase in lecithin:cholesterol acyltransferase reduced by supply of Paigen's diet. Supplementation of PPE and α-asarone enhanced the transcription of hepatic apoA1 and SR-B1 reduced by Paigen's diet in apoE-deficient mice. CONCLUSIONS: α-Asarone in PPE inhibited inflammation-associated atheroma formation and promoted hepatic HDL-C trafficking in dyslipidemic mice.

• Journal of Microbiology and Biotechnology
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• v.17 no.6
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• pp.1024-1030
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• 2007

We investigated the human apolipoprotein E2 (apoE2) transgenic mouse as an animal model system for age-related macular degeneration (AMD). Transgenic mice expressing human apoE2 and C57BL/6J mice were fed normal chow or a high-fat diet for 4 weeks. Eyes were collected from the mice and lipid deposits in retinal pigment epithelium (RPE) were assessed using electron microscopy. The expressions of apoE, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and pigment-epithelium derived factor (PEDF), which are molecular markers for angiogenesis, were assessed with immunohistochemistry. Eyes from apoE2 mice, regardless of diet, contained lipid accumulation in RPE under electron microscopy, whereas control C57BL/6J eyes did not. Lipid accumulation was found predominantly in the RPE and the Bruch's membrane and increased in the eyes of apoE2 mice after one month of a high-fat diet ($8{\pm}2\;per\;50{\mu}m^2$ for normal chow and $11{\pm}2\;per\;50\;{\mu}m^2,\;p<0.05)$. ApoE expression was similar in the apoE2 and control mice; however, VEGF and bFGF were overexpressed in the retinal pigment epithelium of apoE2 eyes compared with control eyes, and PEDF expression was slightly decreased. These expression patterns of VEGF, bFGF, and PEDF suggest angiogenesis is progressing in apoE2 eyes. In conclusion, the eyes of apoE2 mice develop typical lipid accumulations, a common characteristic of AMD, making them a suitable animal model for AMD. The expression profile of VEGF and bFGF on the retinal pigment epithelium suggests that apoE2 may induce neovascularization by altering angiogenic cytokines.

• Journal of Nutrition and Health
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• v.44 no.6
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• pp.465-473
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• 2011

Dietary fatty acids are under intense research to identify anti-atherogenic mechanisms, so we investigated green tea powder (GT) as a protector against atherogenesis originating from lipid peroxidation such as 4-hydroxynonemal (4-HNE) and malondialdehyde (MDA) in different dietary fatty acid-treated apo E KO mice. Growth rate and dietary efficiency were lower in apo E KO mice with or without LA compared to wild type. Plasma total cholesterol (TC) and triacylglycerol (TG) did not correspond to values in other tissues, but TG in heart tissue decreased significantly by GT after linoleic acid (LA) or docosahexaenoic acid (DHA) was administered. LA induced apoptosis as evidenced by changes in aorta morphology and immunohistochemistry. Lipid peroxides (LPO) was increased in apo E KO mice with or without LA corresponding to the accumulation of 4-HNE or MDA in the proximal aorta above the atria. GT consumption tended to reduce the primary causal mechanism of atherogenic phenomena such as oxidizability in both LA and DHA treated atherogenic mice. A high polyunsaturated fatty acids (PUFA) diet involved the changes on stress-induced apoptotic signaling by increasing caspase 3, cytochrome c, and nuclear factor-${\kappa}B$ in the heart tissue, but decreasing the bcl-2 protein. However, GT remarkably reduced the expression of apoptotic signaling, in contrast to the PUFA diet. Therefore, the potential of GT as an anti-atherosclerotic dietary antioxidant was tested in this study.

• Journal of the Korean Society of Food Science and Nutrition
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• v.37 no.11
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• pp.1415-1421
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• 2008

Preventive effects of 3-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid (HDMPPA), an active compound in Korean cabbage kimchi with anti-atherogenic effects, on the accumulation of lipids in the vital organs of $apoE^{(-/-)}$ mice fed atherogenic diet (AD) were studied. Each group of 10 mice was fed AD for 8 weeks with intraperitoneal injection of either HDMPPA (1 mg HDMPPA/100 g BW/day) or phosphate buffered saline as a vehicle. The organs used for this study were liver, kidney, spleen, lung, testis, and brain. Total cholesterol (TC) concentration of lung was the highest followed by spleen and brain. TC level for the liver was the lowest. In contrast to the results of TC, triglyceride (TG) concentration in the liver was the highest followed by kidney and testis. $ApoE^{(-/-)}$ mice did not have any problem uptaking chylomicron remnant by the liver which carries an extra TG after delivering it to the adipose tissue. HDMPPA retarded TC and TG accumulations in the vital organs. Thiobarbituric acid reactive substances (TBARS) in the brain and spleen were the highest and that in the testis were the lowest. Poly-unsaturated fatty acids in the brain and activated peroxisome in the spleen might be responsible for high TBARS levels in these organs. The greatest antioxidant effect of HDMPPA against lipid peroxidation was observed in the spleen, showing 21.47% decrease. The most noticeable effect of HDMPPA was observed in glutathione (GSH) level. GSH levels of six organs in the HDMPPA group were significantly higher than those of the control group. GSH-peroxidase activity was negatively related to GSH level of the organs except liver and spleen. In conclusion, HDMPPA from Korean cabbage kimchi inhibits the lipid accumulation as well as increases the antioxidant status in the vital organs of $apoE^{(-/-)}$ mice fed an atherogenic diet.

• BMB Reports
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• v.51 no.10
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• pp.520-525
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• 2018

Cardiovascular diseases arising from atherosclerosis are the leading causes of mortality and morbidity worldwide. Lipid-lowering agents have been developed in order to treat hypercholesterolemia, a major risk factor for atherosclerosis. However, the prevalence of cardiovascular diseases is increasing, indicating a need to identify novel therapeutic targets and develop new treatment agents. Adenosine receptors (ARs) are emerging as therapeutic targets in asthma, rheumatoid arthritis, cancer, ischemia, and inflammatory diseases. This study assessed whether LJ-1888, a selective antagonist for $A_3$ AR, can inhibit the development of atherosclerosis in apolipoprotein E knock-out ($ApoE^{-/-}$) mice who are fed a western diet. Plaque formation was significantly lower in $ApoE^{-/-}$ mice administered LJ-1888 than in mice not administered LJ-1888, without any associated liver damage. LJ-1888 treatment of $ApoE^{-/-}$ mice prevented western diet-induced hypercholesterolemia by markedly reducing low-density lipoprotein cholesterol levels and significantly increasing high-density lipoprotein cholesterol concentrations. Reduced hypercholesterolemia in $ApoE^{-/-}$ mice administered LJ-1888 was associated with the enhanced expression of genes involved in bile acid biosynthesis. These findings indicate that LJ-1888, a selective antagonist for $A_3$ AR, may be a novel candidate for the treatment of atherosclerosis and hypercholesterolemia.

• Journal of Nutrition and Health
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• v.41 no.7
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• pp.594-601
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• 2008

Panax ginseng C.A. Meyer (Panax ginseng) has been used for several thousand years to prolong longevity in Asian countries. Ginsenosides are the most active components isolated from ginseng and belong to damarane saponin which are separated into protopanaxadiol and protopanaxtriol. To evaluate the complex effect of ginsenoside in apo E null mice, ginseng extract were intraperioneally (i.p.) injected and provided high-cholesterol diet for 12 weeks. Ginseng extract came from were i.p. injected with dose of 100 mg/kg/day for 4 weeks in the last experimental duration. Ginseng extract used experiment was abundant Rb1, Rc, Re, and Rg1 and PD：PT ratio was 1.2. The high-cholesterol diet induced liver damage was significantly reduced by ginseng extract. Results from plasma lipid profiles and atherogenic index were improved by ginseng extracts. The GE group significantly decreased plasma TG and TC by 73% and 61% compared to apo E (-/-) group. Also ginseng extract tend to decrease lipid profiles and lipidperoxidation contents in liver and heart. Ginseng extract with an abundant amount of Rg1 significantly suppressed the apoptosis induction of cardiac tissue. In conclusion, ginseng extract (PD：PT = 1) was improved lipid profiles and anti-oxidant effects.

• Korean Journal of Pharmacognosy
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• v.44 no.4
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• pp.397-401
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• 2013

The Galkun-Whanglyeon-Whanggum-Tang, an officially standardized mixture of traditional herbal medicines used in Korea and China, consists of Pueraria lobata, Scullellaria baicalensis, Coptis chinensis and Glycyrrhiza uralensis at a ratio of 6:9:3:2.4. In this study, we evaluated the effect of lowering lipid accumulation in blood by treatment of Galkun-Whanglyeon-Whanggum-Tang in Apo E(-/-) atherosclerotic animal model. ApoE/mice fed with 1.25% cholesterol, 7.5% cocoa butter and 0.5% sodium cholate diet were orally given vehicle or Galkun-Whanglyeon-Whanggum-Tang(10, 100 and 300 mg/kg/day) for 12 weeks. Serum levels of triglyceride(TG), total cholestrerol(TC), low-density lipoprotein(LDL) and high-density lipoprotein(HDL) were analyzed, and PPAR-${\alpha}$ and PPAR-${\gamma}$ were examined by Western blotting analysis. Galkun-Whanglyeon- Whanggum-Tang decreased serum levels of TG, TC and LDL, but not HDL in ApoE/mice. In parallel, Galkun-Whanglyeon-Whanggum-Tang treatment showed the increased activity of PPAR-${\alpha}$ and PPAR-${\gamma}$ in hepatocytes. In summary, Galkun-Whanglyeon-Whanggum-Tang can reduce lipid accumulation in blood, and this effect might be accompanied by the upregulation of PPAR-${\alpha}$ and PPAR-${\gamma}$ in Apo E(-/-) atherosclerotic mouse model.

• Nutrition Research and Practice
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• v.15 no.3
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• pp.319-328
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• 2021

BACKGROUND/OBJECTIVES: Curcuma zedoaria R. (Zingiberaceae) has been used to treat headache, fever, and hypertension-related symptoms in Asian countries, including Korea, China, and Japan. We investigated whether dietary intake of a C. zedoaria extract (CzE) affected atherosclerosis in vivo. MATERIALS/METHODS: Apolipoprotein E-deficient (ApoE^-/-) mice (n = 32) were fed a normal diet (ND), a high-cholesterol diet (HCD), an HCD containing CzE (100 mg/kg/day), or an HCD containing simvastatin (10 mg/kg/day) for 12 weeks. The anti-atherosclerotic effects were evaluated by observing changes in fatty streak lesions, immunohistochemical analysis, ex vivo fluorescence imaging, lipid profiles, and western blot analysis. RESULTS: The CzE-fed group showed a 41.6% reduction of atherosclerosis. Furthermore, CzE significantly reduced the levels of serum triglyceride, high-density lipoprotein, the chemokine (C-X3-C-motif ) ligand 1, the adhesion molecules vascular cell adhesion molecule-1, intracellular adhesion molecule-1, and E-selectin; down-regulation of tumor necrosis factor-α, interleukin-6, high mobility group box-1, and cathepsin levels in the aortic sinuses and aortas of ApoE^-/- mice were also observed. CONCLUSIONS: The results suggest that the inclusion of a water extract of C. zedoaria in a HCD is closely correlated with reducing the risk of vascular inflammatory diseases in an ApoE mouse model.