• Nutrition Research and Practice
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• 제18권2호
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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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• 제17권6호
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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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• 제17권6호
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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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• 제44권6호
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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.

• 한국식품영양과학회지
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• 제37권11호
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• pp.1415-1421
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• 2008

본 연구는 동맥경화를 억제하는 것으로 보고된 김치 활성성분인 HDMPPA가 동맥경화 식이를 섭취한 $apoE^{(-/-)}$ mice의 주요 장기(동맥제외)에서 지질 축적 억제 및 항산화 효과를 살펴보았다. $ApoE^{(-/-)}$ mice는 1% 콜레스테롤과 10% 라드를 함유한 합성식이를 8주간 섭취하면서 HDMPPA(1 mg/BW/day)를 복강 주사하였고 대조군은 동일양의 PBS를 주사하였다. 간, 신장, 비장, 폐, 고환 그리고 뇌 조직에서 콜레스테롤, 중성지질, TBARS, 총 GSH 농도 및 GSH-peroxidase 활성을 측정하였다. 대조군의 콜레스테롤 농도는 폐, 비장 그리고 뇌에서 높았으며 간이 가장 낮았는데 이러한 경향은 HDMPPA군에서도 동일하게 관찰되었으나 축적된 콜레스테롤 농도는 낮았다. HDMPPA의 콜레스테롤 축적 억제 효과는 간(22.65%, p<0.01), 비장(11.73%, p<0.05), 그리고 뇌(15.34%, p<0.05)에서 유의적으로 관찰되었다. 이에 반해 중성지질의 농도는 간, 신장 그리고 고환에서 높아 총콜레스테롤 축적과 다른 양상을 보였는데 이는 apo $E^{(-/-)}$ 마우스의 간이 중성지질을 함유한 지단백질을 받아들이는데는 문제가 없기 때문으로 생각된다. HDMPPA군의 간(14.7%, p<0.05), 신장(22.83%, p<0.001) 그리고 비장(35.87%, p<0.05)의 중성지질 농도는 유의적으로 낮았다. 지질과산화물 농도(TBARS)는 불포화지방산을 다량 함유한 뇌와 peroxisome이 발달하여 활성산소의 생성이 높은 비장에서 가장 높았으며 항산화물질을 다량 함유하고 있는 고환이 가장 낮았다. HDMPPA군의 비장의 TBARS 농도는 대조군에 비해 21.47%(p<0.01) 유의적으로 낮았다. GSH 농도는 고환, 간, 그리고 신장에서 높아 TBARS 결과와 반대였다. GSH-px 활성이 높은 장기의 GSH 농도는 낮은 편이었으나 간과 비장은 예외였다. HDMPPA군의 GSH 농도는 대조군에 비해 모든 장기에서 유의적으로 높았는데 이는 알려져 있는 HDMPPA의 항산화작용 때문으로 생각된다. 이상의 결과로부터 김치의 활성 성분인 HDMPPA는 동맥경화유발 식이를 섭취한 $apoE^{(-/-)}$ mice의 주요 장기에서 지질축적을 억제하며 체내 항산화 작용을 돕는 효과가 있음을 확인하였다.

• BMB Reports
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• 제51권10호
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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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• 제41권7호
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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.

• 생약학회지
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• 제44권4호
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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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• 제15권3호
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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.

• Asian Pacific Journal of Cancer Prevention
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• 제16권4호
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• pp.1375-1383
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• 2015

Background: Objective Myocardin-related transcription factor (MRTF)-A is a Rho signaling-responsive co-activator of serum response factor (SRF). The purpose of this study is to investigate the role of MRTF-A and AQP1 (aquaporin 1) in pathological vascular remodeling. Materials and Methods: MRTF-A, AQP1 and neointima expression was detected both in the wire injured femoral arteries of wild-type mice and the atherosclerotic aortic tissues of $ApoE^{-/-}$ mice. Expression of ICAM-1, matrix metallopeptidase 9 (MMP-9) and integrin ${\beta}1$ were also assayed. The intercourse relationship between the molecules were investigated by interfering RNA and inhibitor assay. Results: MRTF-A and AQP1 expression were significantly higher in the wire injured femoral arteries of wild-type mice and in the atherosclerotic aortic tissues of $ApoE^{-/-}$ mice than in healthy control tissues. Both in wire-injured femoral arteries in MRTF-A knockout ($Mkl1^{-/-}$) mice and atherosclerotic lesions in $Mkl1^{-/-}$; $ApoE^{-/-}$ mice, neointima formation were significantly attenuated and the expression of AQP1 were significantly decreased. Expression of ICAM-1, matrix metallopeptidase 9 (MMP-9) and integrin ${\beta}1$, three SRF targets and key regulators of cell migration, and AQP1 in injured arteries was significantly weaker in $Mkl1^{-/-}$ mice than in wild-type mice. In cultured vascular smooth muscle cells (VSMCs), knocking down MRTF-A reduced expression of these genes and significantly impaired cell migration. Underlying the increased MRTF-A expression in dedifferentiated VSMCs were the down-regulation of microRNA-300. Moreover, the MRTF-A inhibitor CCG1423 significantly reduced neointima formation following wire injury in mice. Conclusions: MRTF-A could be a novel therapeutic target for the treatment of vascular diseases.