Anti-atherosclerosis Effects Research Articles

C1q/TNF-related protein-9 attenuates retinal inflammation and protects blood–retinal barrier in db/db mice

C1q/TNF-related protein-9(CTRP9) is an adipose cytokine, a closest adiponectin paralog, which has anti-inflammatory, antioxidant, vasodilation and anti-atherosclerosis effects. In addition, it can increase insulin sensitivity, decrease blood glucose level and inhibit the apoptosis of endothelial cells. However, it remains unclear whether CTRP9 has beneficial effects on diabetic retinopathy (DR). An adenoviral vector expressing CTRP9 was intravenously injected into db/db mice, aged 12 weeks, at day 15 post injection, and the process was repeated. The transfection efficiency of CTRP9 was assessed by enzyme linked immunosorbent assay. We used RT-PCR, immunofluorescence, and Western blot to determine proinflammatory cytokines, adhesion molecules and tight-junction proteins. The breakdown of blood–retinal barrier (BRB) was evaluated using Evans blue and retinal staining. CTRP9 suppresses the expression of interleukin-1 beta, tumor necrosis factor-alpha, monocyte chemotactic protein-1 and adhesion molecules in the retina of db/db mice. CTRP9 can balance the expression of pigment epithelium-derived factor and vascular endothelial growth factor. CTRP9 can also inhibit the activation of nuclear factor Kappa B in the retina of db/db mouse. In addition, CTRP9 can prevent the breakdown of BRB and downregulation of tight-junction proteins in the retina of db/db mice. Evans blue assay revealed the breakdown of BRB and vascular leakage in the retinas of diabetic mice. CTRP9 can both qualitatively and quantitatively alleviate the vascular leakage in the early stage of diabetic retinas. CTRP9 can inhibit the inflammation of diabetic retinopathy and protect blood–retinal barrier via decreasing proinflammatory cytokines and preventing the downregulation of tight-junction proteins.

Appropriate dose of ethanol exerts anti-senescence and anti-atherosclerosis protective effects by activating ALDH2

Moderate alcohol consumption has been shown to reduce atherosclerosis-associated diseases. As shown in our earlier works, ethanol has a dose-dependent protective effects against endothelial cellular senescence by activating aldehyde dehydrogenase 2 (ALDH2) in vitro. However, whether ethanol administration possesses anti-atherosclerosis properties and whether ALDH2 is involved in the underlying mechanisms are unknown. In the present study, we revealed that the appropriate dose of ethanol reduced atherosclerotic plaque formation, and upregulated ALDH2 expression and activity in ApoE-/- mice. ALDH2 deficiency blocked the protection of ethanol against atherosclerotic plaque formation by inhibiting endothelium senescence. In contrast, Alda-1, which is a specific enzymatic agonist of ALDH2, enhanced the anti-senescence and anti-atherosclerosis effects of the appropriate dose of ethanol. Furthermore, following ALDH2 knockdown, resveratrol (an anti-aging compound) recovered the beneficial effects of ethanol against endothelial senescence in vitro. Thus, these results suggest that the appropriate dose of ethanol has protective effects against endothelial senescence and atherosclerosis by activating ALDH2.

Z-Ligustilide protects vascular endothelial cells from oxidative stress and rescues high fat diet-induced atherosclerosis by activating multiple NRF2 downstream genes

Background and aimsOxidative stress-induced endothelial dysfunction is considered to exert a vital role in the development of atherosclerotic coronary heart disease (CHD). NRF2 is a key transcriptional factor against oxidative stress through activation of multiple ARE-mediated genes. Z-Lig is derived from the Ligusticum species with antitumor, anti-inflammation and neuroprotection activities. However, the antioxidant potentials of Z-Lig on endothelial dysfunction and atherosclerosis have not been well elucidated. Therefore, in the present work, we appraise the cytoprotective property and anti-atherosclerosis effect of Z-Lig. MethodsPotential NRF2 activators were screened and verified by luciferase reporter gene assay. The protein and mRNA levels of NRF2 and ARE-mediated genes, and GSH/GSSG level in EA.hy926 cells treated with Z-Lig were detected. The cytoprotective property of Z-Lig was assessed in the tert-butyl hydroperoxide (t-BHP)-evoked oxidative stress model. Cell viability and reactive oxygen species (ROS) levels in EA.hy926 cells were determined. An atherosclerosis model induced by HFD was used to determine the anti-atherosclerosis effect of Z-Lig in HFD-fed Ldlr-deficient mice. ResultsIn vitro, 100 μM Z-Lig upregulated expressions of NRF2 and ARE-driven genes, promoted accumulation of nuclear NRF2 and unbound NRF2- KEAP1 complex in EA.hy926 cells. Furthermore, Z-Lig alleviated oxidative stress and cell injury caused by t-BHP via stimulation of the NRF2/ARE pathway. In vivo, intervention with 20 mg/kg Z-Lig markedly restrained atherosclerosis progression, including attenuation of HFD-induced atherosclerotic plaque formation, alleviation of lipid peroxidation and increase in antioxidant enzyme activity in aortas of HFD-fed Ldlr−/− mice. The chemopreventive effects of Z-Lig might be associated with the activation of NRF2 and ARE-driven genes. ConclusionsThe present study suggested that Z-Lig is an effective NRF2 activator, which can protect vascular endothelial cells from oxidative stress and rescue HFD-induced atherosclerosis.

Determination of process parameters and bioactive properties of the murici pulp (Byrsonima crassifolia) extracts obtained by supercritical extraction

The obtaining of muruci extracts (Byrsonima crassifolia) was performed by CO2-SFE and CO2+EtOH-SFE, which were conducted at 323.15 K–343.15 K, and at 15 MPa to 49 MPa. The increase of 50% in the solvent flow rates, and the reduction of 33% in the dynamic period increased the yields. For the CO2-SFE, the highest values of global yield (9.12%), lutein (207.18 μg/g), and antioxidants (33.91 μmol TE/g) were obtained at 333.15 K. In the CO2+EtOH-SFE of the defatted freeze dried murici pulp, the highest values of lutein (209.73 μg/g), phenolics (43.69 mg GAE/g), and antioxidants (138.85 μmol TE/g) were obtained at 940 kg/m3, with a strong positive phenolics/antioxidants correlation. The functional quality suggests hypercholesterolemic, antiatherosclerosis and antithrombogenic effects.

Cyanidin-3-O-β-glucoside attenuates allergic airway inflammation by modulating the IL-4Rα-STAT6 signaling pathway in a murine asthma model

Cyanidin-3-O-β-glucoside (Cy-3-g), a typical and abundant monomer of anthocyanins, exhibits a variety of biological activities, such as anti-atherosclerosis, anti-obesity, and anticancer effects. However, to date little is known about its effects on asthma. This study aimed to investigate the efficacy of dietary Cy-3-g on allergic asthma in an animal model. BALB/c mice were sensitized and challenged with ovalbumin (OVA) to induce allergic asthma. The pathological changes of the lung tissues, type 2 helper (Th2)-associated cytokine production in bronchoalveolar lavage fluid (BALF), and the interleukin 4 receptor alpha (IL-4Rα)-signal transducer and activator of transcription 6 (STAT6) signaling pathway activities were assessed. We found that Cy-3-g significantly inhibited OVA-induced inflammatory cell infiltration and mucus hyper-production in lung tissues, reduced the production of interleukin 4 (IL-4), interleukin 5 (IL-5) and interleukin 13 (IL-13) in BALF. Furthermore, Cy-3-g effectively suppressed OVA-induced up-regulation of the IL-4Rα-STAT6 signaling pathway activity of the lung tissues. These results demonstrated that dietary Cy-3-g could attenuate allergic airway inflammation in a murine asthma model, and Cy-3-g might be used as an agent for asthma prevention and/or treatment in the future.

Effects of Xuezhikang (Red Yeast Rice) on Blood lipids, Hemorheology and the Expression of P65 and Tissue Factor in Atherosclerotic Rats

Objective: To observe the effects of Xuezhikang (red yeast rice) on blood lipids, blood rheology, and expression of P65 and tissue factor, and to explore the anti-atherosclerosis effect and related mechanisms of Xuezhikang (red yeast rice). Methods: 32 Wistar rats were randomly divided into normal control group, Xuezhikang treatment group, lovastatin treatment group and atherosclerosis model group (8 in each group). blood lipids, blood rheology, malondialdehyde (MDA), total antioxidant capacity (t-AOc), and expression of aortic tissue factor (tF) and P65 were measured in each group. results: (1) Both Xuezhikang and lovastatin could reduce blood lipid levels, but there was no significant difference between the two groups; (2) Both Xuezhikang and lovastatin can improve the hemorheology of atherosclerotic rats, but the difference between the two groups is not signifcant; (3) Compared with lovastatin, Xuezhikang inhibited the expression of TF and P65 in aorta of rats with atherosclerosis; (4) Compared with lovastatin, the Xuezhikang group had lower MDA levels and higher T-AOC. Conclusion: Xuezhikang can improve blood lipid levels and hemorheology in rats with atherosclerosis. Compared with lovastatin, Xuezhikang has stronger effects on inhibiting oxidative stress and down-regulating the expression of tissue factor and P65.

Standardized Xin-Ke-Shu tablets improves the disturbances of lipid, energy, and amino acid metabolism in a rabbit model of atherosclerosis

Objective: Xin-Ke-Shu (XKS), a patent drug, used to treat coronary artery diseases in China for many years. Previous research indicates that XKS has similar therapeutic effect as atorvastatin (AS) against atherosclerotic in rabbits. However, biochemical assays demonstrate that XKS could have a different therapeutic mechanism from AS. The aim of this study is to explore the mechanism of XKS therapeutic effect, especially those different from AS. Materials and Methods:1H nuclear magnetic resonance-based metabonomics were applied to profile the low-molecular-weight polar metabolites in the plasma of rabbits fed a high cholesterol diet. Results: Seven of the eleven pathological biomarkers related to atherosclerosis in rabbits were mediated by XKS treatment, namely low-density lipoprotein/very-low-density lipoprotein (LDL/VLDL), lactate, citrate, phosphatidylcholine, glutamine, creatinine, and methionine, as well as two characteristic metabolites of pyruvate and α-glucose. These metabolites involved lipid, energy, and amino acid metabolism, and all could be considered XKS treatment targets. However, AS only affected the metabolic disorders associated with LDL/VLDL and phosphatidylcholine, which is mainly target lipid metabolism. Conclusions: This study indicates that the anti-atherosclerosis effects of AS mainly involve reducing blood–lipid levels, but those of XKS involve a multitargeted activity.

Eicosapentaenoic acid in the form of phospholipids exerts superior anti-atherosclerosis effects to its triglyceride form in ApoE−/−mice

Dietary eicosapentaenoic acid (EPA), a main component of fish oil, has been proved to reduce the risk of cardiovascular disease. The purpose of this study was to investigate whether the anti-atherosclerosis effect of fish oil enriched with EPA partially relied on its chemical groups at the sn-3 position. Male ApoE-/- mice were divided into three groups and were fed a high-fat diet (Model) or a high-fat diet containing EPA incorporated into phospholipids (EPA-PL) or triglycerides (EPA-TG), respectively. Compared with the model group, a decrease in the area of atherosclerosis lesions at the aorta was observed in both EPA-treated groups, in which EPA-PL was superior to EPA-TG. Notably, EPA-PL exhibited lower serum and hepatic lipid levels than the model group, whereas EPA-TG only reduced the hepatic triglyceride level. Interestingly, only EPA-PL treatment regulated the expression of genes involved in cholesterol metabolism. In addition, EPA-PL and EPA-TG suppressed the inflammation markers in the aorta and circulation. In conclusion, EPA-PL was superior to EPA-TG in reducing lesion progression by modulating the hepatic lipid metabolism, as well as decreasing the inflammation in the artery wall and circulatory system, which might be attributed to their structural differences at the sn-3 position.

Synergistic effects of liposomes encapsulating atorvastatin calcium and curcumin and targeting dysfunctional endothelial cells in reducing atherosclerosis

BackgroundAtherosclerosis is a major cardiovascular disease that causes ischemia of the heart, brain, or extremities, and can lead to infarction. The hypolipidemic agent atorvastatin calcium (Ato) alleviates atherosclerosis by reducing plasma lipid and inflammatory factors. However, the low bioavailability of Ato limits its widespread use and clinical effectiveness. Curcumin (Cur), a natural polyphenol with antioxidation and anti-inflammation bioactivities, has potential anti-atherosclerosis activity and may reduce Ato-induced cytotoxicity.Materials and methodsLiposomes modified using a targeting ligand (E-selectin-binding peptide) were prepared to co-deliver Ato and Cur to dysfunctional endothelial cells (ECs) overexpressing E-selectin. Molecules involved in the inhibition of adhesion (E-selectin and intercellular cell adhesion molecule-1 [ICAM-1]) and inflammation (IL-6 and monocyte chemotactic protein 1 [MCP-1]) in human aortic endothelial cells were evaluated using real-time quantitative PCR, flow cytometry, and immunofluorescence staining. The antiatherosclerosis effects of liposomes co-loaded with Ato and Cur in vivo were evaluated using ApoE knockout (ApoE−/−) mice.ResultsTargeted liposomes delivered Ato and Cur to dysfunctional ECs, resulting in synergistic suppression of adhesion molecules (E-selectin and ICAM-1) and plasma lipid levels. Moreover, this treatment reduced foam cell formation and the secretion of inflammatory factors (IL-6 and MCP-1) by blocking monocyte migration into the intima. In addition, Cur successfully reduced Ato-inducible cytotoxicity.ConclusionBoth in vitro and in vivo experiments demonstrated that cell-targeted co-delivery of Ato and Cur to dysfunctional ECs drastically reduces atherosclerotic lesions with fewer side effects than either Ato or Cur alone.

Paeonol Attenuated Inflammatory Response of Endothelial Cells via Stimulating Monocytes-Derived Exosomal MicroRNA-223.

Introduction: Paeonol, an active compound isolated from the radix of Cortex Moutan, has been shown to have anti-atherosclerosis effects by regulating blood cells’ function and protecting vascular cells injury. Besides, emerging evidences has proven that exosomes might play a pivotal role in intercellular communication by transmiting proteins and microRNAs from cell to cell. However, the relationship between monocytes-derived exosomal microRNA-223 and vascular inflammation injury along with paeonol’ effects are still not clear.Objective: Our study aimed to explain whether paeonol’s protective effect on inflammatory response is related to the regulation of exosomal microRNA-223 in the VECs.Methods: ApoE−/− mice were fed with high fat diet to replicate the AS model. HE staining and immunohistochemistry was used to detect inflammatory response of aorta. The expression of IL-1β and IL-6 were detected by ELISA. Western blot was used to detect the expression of STAT3, pSTAT3, ICAM-1 and VCAM-1. qRT-PCR was used to detect miR-223 expression. Exosomes were extracted from THP-1 cells by differential centrifugation and observed by transmission electron microscope. Observation of exosomes uptake into HUVECs was realized by laser microscopy. miR-223 target gene was detected by double luciferase gene report test.Results: In vivo experiments confirmed that paeonol restricted atherosclerosis development and increased miR-223 expression, inhibited STAT3 pathway in ApoE−/− mice. In vitro, miR-223 showed robust presence in THP-1 cells and undetectable in HUVECs. And we had observed that miR-223 could be internalized from THP-1 cells into HUVECs taking exosomes as a carrier. Paeonol obviously increased miR-223 expression in co-cultured HUVECs and exosomes in concentration dependent manner, compared to LPS group. In addition, paeonol relieved inflammatory secretion, adhesion and STAT3 expression in HUVECs, which could be inverted after miR-223 inhibitor transfection into THP-1 cells.Conclusion: Paeonol could increase the expression of miR-223 in THP-1 derived exosomes and in HUVECs after uptake of exosomes, whereas decrease the expression of STAT3, p-STAT3 in HUVECs. Ultimately paeonol decreased the expression of IL-1β, IL-6, ICAM-1, VCAM-1 in HUVECs and alleviated adhesion of THP-1 cells to HUVECs.

Research progress of combined statins and clopidogrel on atherosclerotic plaques

Statins and antiplatelet drugs are the two cornerstones for the treatment of cerebrovascular diseases.This two drugs play a vital role in reducing platelet reactivity and inhibiting inflammation.Statins can effectively delay the progression of atherosclerosis, reduce plaque volume and reduce the incidence of cerebrovascular diseases through multiple pathways.Clopidogrel is currently used primarily for anti-platelet aggregation.Some studies indicate that clopidogrel is also involved in the process of atherosclerosis, but the mechanism is not clear.The anti-atherosclerosis effect of clopidogrel is often neglected, when statins are combined with clopidogrel.This article reviews the progress in the treatment of atherosclerotic plaque by statin combined with clopidogrel. Key words: Atherosclerosis; Statins; Clopidogrel; Cerebrovascular disease; Plaques

Platelet membrane-coated nanoparticle-mediated targeting delivery of Rapamycin blocks atherosclerotic plaque development and stabilizes plaque in apolipoprotein E-deficient (ApoE−/−) mice

Although certain success has been achieved in atherosclerosis treatment, tremendous challenges remain in developing more efficient strategies to treat atherosclerosis. Platelets have inherent affinity to plaques and naturally home to atherosclerotic sites. Rapamycin features potent anti-atherosclerosis effect, but its clinical utility is limited by its low concentration at the atherosclerotic site and severe systemic toxicity. In the present study, we used platelet membrane-coated nanoparticles (PNP) as a targeted drug delivery platform to treat atherosclerosis through mimicking platelets' inherent targeting to plaques. PNP displayed 4.98-fold greater radiant efficiency than control nanoparticles in atherosclerotic arterial trees, indicating its effective homing to atherosclerotic plaques in vivo. In an atherosclerosis model established in apolipoprotein E-deficient mice, PNP encapsulating rapamycin significantly attenuated the progression of atherosclerosis and stabilized atherosclerotic plaques. These results demonstrated the perfect efficacy and pro-resolving potential of PNP as a targeted drug delivery platform for atherosclerosis treatment.

Absorption of polymethoxyflavones and their derivatives

Polymethoxyflavones (PMFs) are a group of flavonoids found exclusively in citrus genus that have been identified with many potent biological activities, including anti-inflammation, anti-cancer, anti-atherosclerosis, and antioxidant effects. However, the bioavailability of PMFs is seldom studied. Evaluating by aqueous solubility and permeability, absorption is the first indicator of bioavailability. In this research, we systemically investigated permeability and solubility of six PMFs and their derivatives, namely, sinensetin (SIN), 5-demethylsinensetin (5-OHSIN), 5-acetylsinensetin (5-AcSIN), 3,5,6,7,8,3′,4′-heptamethoxyflavone (HeptaMF), 5-hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone (5-OHHeptaMF), and 5-acetyl-3,6,7,8,3′,4′-hexamethoxyflavone (5-AcHeptaMF). From octanol/water solubility test, we found that PMFs and their derivatives had very low aqueous solubility. Permeability experiment via Caco-2 cell monolayer transport model indicated high permeability of all the tested compounds. Furthermore, PMFs had the greatest permeability, followed by 5-acetyl PMFs and 5-hydroxylated PMFs. Considering permeability and solubility together, PMFs and their derivatives are expected to have good absorption. This study provides indicative information on the bioavailability of PMFs and their derivatives, which offers clues on the application of PMFs in functional food or nutraceutical products.

A systematic review on the rhizome of Ligusticum chuanxiong Hort. (Chuanxiong)

Chuanxiong Rhizome (called Chuanxiong, CX in Chinese), the dried rhizome of Ligusticum chuanxiong Hort, is an extremely common traditional edible-medicinal herb. As a widely used ethnomedicine in Asia including China, Japan and Korea, CX possesses ideal therapeutic effect on cardiovascular and cerebrovascular diseases, and is also used as a major ingredient in soups for regular consumption to benefit health. Based on the traditional perception, amounts of investigations on different aspects have been done for CX in the past decades. However, no literature systematic review about these achievements have been compiled. Herein, the aim of this review is to present the up-to-date information on the ethnobotany, ethnopharmacological uses, phytochemicals, pharmacological activities, toxicology of this plant to identify their therapeutic potential and directs future research opportunities. So far, about 174 compounds has been isolated and identified from CX, in which phthalides and alkaloids would be the main bioactive ingredients for its pharmacological properties, such as anti-cerebral ischemia, anti-myocardial ischemia, blood vessel protection, anti-thrombotic, anti-hypertensive, anti-atherosclerosis, anti-spasmodic, anti-inflammatory, anti-cancer, anti-oxidant, and anti-asthma effects. Even so, due to the incomplete standardized planting, unstable herbal quality, and outdated preparation techniques, the industrial progress of CX is still less developed.

Inhibitory Effects of an Orally Active Thromboxane A2 Receptor Antagonist, nstpbp5185, on Atherosclerosis in ApoE-Deficient Mice.

Thromboxane A2 (TXA2) activation of TP receptor has been shown contributing to the progression and acute complications of atherosclerosis including endothelial dysfunction, platelet hyperactivity and inflammation. Growing evidence suggests that TP receptor may represent as a therapeutic target in atherosclerosis and related cardiovascular diseases. We investigated whether nstpbp5185, an orally active TP receptor antagonist, exhibits protective effects against atherosclerotic progression. Nstpbp5185 and aspirin were orally administered daily for 12 weeks in high-cholesterol-fed ApoE-deficient mice to examine their anti-atherosclerosis effects. Total cholesterol, low-density lipoprotein cholesterol and triglycerides were slightly decreased in nstpbp5185-treated mice. However, nstpbp5185 significantly reduced neointima formation and aortic atherosclerotic lesion area. Nstpbp5185 increased serum paraoxonase 1 activity. In contrast, plasma levels of interleukin-6 and tumour necrosis factor-α were reduced in nstpbp5185-treated mice. Plasma level of TXA2 metabolite, TXB2, was lower in both aspirin- and nstpbp5185-treated mice, while the urinary 2,3-dinor-6-keto PGF1α (a PGI2 metabolite) and plasma iPF2α-III were not altered. Moreover, nstpbp5185 neither caused gastric ulceration nor affected the haemostatic response. Nstpbp5185 also inhibited U46619-induced endothelial NF-kB activation, ICAM-1 and VCAM-1 expression, as well as monocyte adhesion to endothelial cells. In conclusion, nstpbp5185 may represent as an ideal, safe and efficacious agent for preventing atherosclerotic progression through its antiplatelet, anti-inflammatory and antioxidative activities.

Flavonoid-rich extract of Polygonum capitatum attenuates high-fat diet–induced atherosclerosis development and inflammatory and oxidative stress in hyperlipidemia rats

This research was carried out to investigate the effects of flavonoids ingredient from Polygonum capitatum (FPC) on blood lipid levels, vascular inflammation, and oxidative stress in high-fat diet (HFD) rats, as well as their mechanism of action. Rats fed with HFD for 6 weeks obviously displayed hyperlipidemia ( P < 0.01). Treatment with FPC at 90 and 180 mg/kg body weight significantly increased serum apolipoprotein A (ApoA) and high-density lipoprotein-cholesterol (HDL-C) levels and decreased serum apolipoprotein B (ApoB), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein-cholesterol (LDL-C) levels of hyperlipidemia rats. FPC also improved the serum superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities and decreased serum malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) levels. Meanwhile, the result of reverse transcription polymerase chain reaction (RT-PCR) manifested that FPC upregulated the messenger RNA (mRNA) expression of low-density lipoprotein receptor (LDLR) and peroxisome proliferator–activated receptor α (PPARα) and downregulated the mRNA expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), acetyl CoA carboxylase (ACC), and sterol regulatory element-binding protein 1c (SREBP-1C) in the hepatic. These results demonstrated that FPC exerted anti-atherosclerosis effect in hyperlipidemia rats by regulating blood lipid metabolism, improving antioxidant ability, and modulating a proinflammatory profile and the expression levels of genes referred to lipogenesis and lipid oxidation, which might be attributed to flavonoid ingredients such as luteolin-7-O-glucoside, rutin, and quercitrin.

Oleanolic acid protects against pathogenesis of atherosclerosis, possibly via FXR-mediated angiotensin (Ang)-(1–7) upregulation

Atherosclerosis, the leading cause of cardiovascular diseases in the world, is a chronic inflammatory disorder characterized by the dysfunction of arteries. Oleanolic acid (OA) is a bioactive nature product which exists in various plants and herbs. Previous studies have demonstrated that OA was involved in numerous of biological processes, including atherosclerosis. However, the exact mechanisms of the anti-atherosclerosis effects of OA remain unknown. Here, in our study, we analyzed the effects and possible underlying mechanisms of OA in atherosclerosis depending a cell model and an animal model of atherosclerosis. Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (ox-LDL, 100 μg/mL) for 24 h to establish an atherosclerotic cell model. New Zealand white (NZW) rabbits were fed with high-fat (HF) diets for three months to establish an atherosclerotic animal model. Then, cell viability and expression of cytokines (ANG, NO, eNOS, IL-1β, TNF-α, and IL-6) were measured with CCK-8 assay and ELISA kits, cell apoptosis and cell cycle distribution were analyzed by flow cytometry in the atherosclerotic cell model. Results showed that ox-LDL induced effects of anti-proliferation, cytokines alterations, and cell apoptosis were abolished by the application of OA or Ang (1–7). Further study indicated that OA increased the expression of ANG by upregulating the FXR expression in the ox-LDL induced HUVECs arthrosclerosis model. And the in vivo experiment in the HF diet induced animal model suggested that OA may inhibit the development of atherosclerosis. The atherosclerosis of aortas was assessed by Hematoxylin Eosin (HE), Oil Red O and Picrosirius Red staining; the expression levels of total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C) were determined by the fully automatic biochemical analyzer, in the atherosclerotic animal model. All the results showed that OA treatment improved the cell viability in the cell model, inhibited the atherosclerosis development in the animal model. OA play as an anti-atherosclerosis agent in both the cell model and animal model by upregulating the production of Angiotensin (Ang)-(1–7) through FXR.

Cadmium exposure exacerbates severe hyperlipidemia and fatty liver changes in zebrafish via impairment of high-density lipoproteins functionality

Cadmium (Cd) is a heavy metal with several toxicities that have destructive effect on most organ systems. However, its toxic effects on human lipoproteins are largely remained unknown especially in hyperlipidemic zebrafish model. Treatment of human high-density lipoprotein (HDL) with cadmium chloride (CdCl2, final 12 and 24μM) caused spontaneous formation of multimeric apoA-I as well as increased production of glycated extent products. Cd-HDL3 accelerated uptake of oxidized LDL (oxLDL) into macrophages and induced severe senescence in human dermal fibroblast (HDF) cells. Microinjection of Cd-HDL3 into zebrafish embryos resulted in acute embryonic toxicity with high mortality. Exposure of zebrafish embryos to water containing CdCl2 (final 12 and 24μM) caused early embryonic death along with increased production of oxidized products and impairment of skeletal development. Consumption of CdCl2 (12 and 24μM) by zebrafish for 4weeks resulted in severe elevation of plasma total cholesterol (TC) and triglyceride (TG) levels as well as cholesteryl ester (CE) transfer activity. Furthermore, consumption of CdCl2 resulted in acceleration of fatty liver changes and increased production of reactive oxygen species (ROS). In conclusion, CdCl2 caused structural modification of HDL3 and impaired the beneficial functions of HDL3, including anti-oxidation, anti-atherosclerosis, and anti-senescence effects. Consumption of CdCl2 also resulted in exacerbated hyperlipidemia and fatty liver changes in zebrafish via enhancement of cholesteryl ester transfer protein (CETP) activity.

Lipid X receptors in atherosclerosis: a review

Atherosclerosis is a chronic inflammatory disease of the vasculature that is characterized by lipid accumulation and plaque development within arteries. Liver X receptors (LXRs), the pivotal regulators of lipid homeostasis in mammals, are members of the nuclear receptor superfamily of DNA-binding transcription factors. Moreover, the activation of LXRs can upregulate the expression of genes related to reverse cholesterol transport (RCT), and promote the cholesterol efflux in macrophages. Additionally, LXRs activation also could inhibit the inflammation in macrophages, epithelial cells, and smooth muscle cells, which contributes to the effect of anti-atherosclerosis. This review is focused on summarizing the development of synthetic LXR agonists and the mechanisms of the activation of LXR in anti-atherosclerosis. Key words: Liver X receptor; Atherosclerosis; Reverse cholesterol transport; Inflammation

UPLC-Q-TOF/MS-based metabonomic studies on the intervention effects of aspirin eugenol ester in atherosclerosis hamsters

Based on the pro-drug principle, aspirin and eugenol were used to synthesize aspirin eugenol ester (AEE) by esterification reaction. In present study, the anti-atherosclerosis effects of AEE were investigated in hamsters with the utilization of metabonomic approach based on UPLC-Q-TOF/MS. Biochemical parameters and histopathological injures in stomach, liver and aorta were evaluated. In atherosclerotic hamster, oral administration of AEE normalized biochemical profile such as reducing TG, TCH and LDL, and significantly reduced body weight gain, alleviated hepatic steatosis and improved pathological lesions in aorta. Slight damages in stomach mucous were found in AEE group. Plasma and urine samples in control, model and AEE groups were scattered in the partial least squares-discriminate analysis (PLS-DA) score plots. Thirteen endogenous metabolites in plasma such as lysophosphatidylcholine (LysoPC), leucine and valine, and seventeen endogenous metabolites in urine such as citric acid, phenol sulphate and phenylacetylglycine were selected as potential biomarkers associated with atherosclerosis. They were considered to be in response to anti-atherosclerosis effects of AEE, mainly involved in glycerophospholipid metabolism, amino acid metabolism and energy metabolism. This study extended the understanding of endogenous alterations of atherosclerosis and offered insights into the pharmacodynamic activity of AEE.