Simvastatin reduces atherogenesis and promotes the expression of hepatic genes associated with reverse cholesterol transport in apoE-knockout mice fed high-fat diet

<p>Abstract</p> <p>Background</p> <p>Statins are first-line pharmacotherapeutic agents for hypercholesterolemia treatment in humans. However the effects of statins on atherosclerosis in mouse models are very paradoxical. In this work, we wanted to evaluate the effects of simvastatin on serum cholesterol, atherogenesis, and the expression of several factors playing important roles in reverse cholesterol transport (RCT) in apoE-/- mice fed a high-fat diet.</p> <p>Results</p> <p>The atherosclerotic lesion formation displayed by oil red O staining positive area was reduced significantly by 35% or 47% in either aortic root section or aortic arch en face in simvastatin administrated apoE-/- mice compared to the control. Plasma analysis by enzymatic method or ELISA showed that high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) contents were remarkably increased by treatment with simvastatin. And plasma lecithin-cholesterol acyltransferase (LCAT) activity was markedly increased by simvastatin treatment. Real-time PCR detection disclosed that the expression of several transporters involved in reverse cholesterol transport, including macrophage scavenger receptor class B type I, hepatic ATP-binding cassette (ABC) transporters ABCG5, and ABCB4 were induced by simvastatin treatment, the expression of hepatic ABCA1 and apoA-I, which play roles in the maturation of HDL-C, were also elevated in simvastatin treated groups.</p> <p>Conclusions</p> <p>We demonstrated the anti-atherogenesis effects of simvastatin in apoE-/- mice fed a high-fat diet. We confirmed here for the first time simvastatin increased the expression of hepatic ABCB4 and ABCG5, which involved in secretion of cholesterol and bile acids into the bile, besides upregulated ABCA1 and apoA-I. The elevated HDL-C level, increased LCAT activity and the stimulation of several transporters involved in RCT may all contribute to the anti-atherosclerotic effect of simvastatin.</p

Inhibitory effect of the combination therapy of simvastatin and pinocembrin on atherosclerosis in apoE-deficient mice

<p>Abstract</p> <p>The present study was performed to investigate the effects of the combination therapy of pinocembrin and simvastatin on the atherosclerotic lesions development in the ApoE^−/− mice.</p> <p>Methods</p> <p>Eight-week-old male ApoE^−/− mice were fed high fat diet (HFD) and treated with simvastatin (10 mg/kg per day), pinocembrin (20 mg/kg per day), or the combination therapy (simvastatin 5 mg/kg per day and pinocembrin 20 mg/kg per day) for 14 weeks. The serum lipid levels, nitric oxide (NO), endothelin (ET), superoxide dismutase (SOD) and malondialdehyde (MDA) were determined with spectrophotometric measurement and ELISA assay. Vascular endothelial growth factor (VEGF) in serum and aortic root was detected. En face analyses of atherosclerotic lesion in whole aorta and aortic root sections were performed with plaque staining using oil red O.</p> <p>Results</p> <p>The combination treatment with simvastatin and pinocembrin resulted in significantly decreased levels of serum total cholesterol, triglycerides and low-density lipoprotein cholesterol, augmented NO levels and SOD activity, inhibited ET and VEGF expression. Immunohistochemistry of aortic valve sections revealed that the combination therapy also suppressed the expression of VEGF induced by HFD. In addition, HFD-induced arterial wall lipid disposition displayed by oil red O staining was reduced significantly in aortic root and whole aorta en face in the combination administrated mice. The effect of the combination was superior to simvastatin alone.</p> <p>Conclusion</p> <p>The combination of simvastatin and pinocembrin synergistically inhibited atherosclerotic lesion development in ApoE^−/− mice with hyperlipidemia, which is partially dependent on the protective of vascular endothelium.</p

Femtosecond laser induced nano-meter size surface structures on ZnSe film

We realize femtosecond laser-induced high spatial frequency nano-meter size periodic surface structures with a periodicity about 140nm-170 nm on ZnSe film in one step. Compared with bulk ZnSe, the periodicity and fluence threshold of the surface structure on ZnSe film are smaller and lower. We propose the shortened melting duration, which caused by the higher thermal conductivity of the sapphire substrate, is the origin of the difference between the bulk ZnSe and ZnSe film. Surface capillary wave is easier frozen with shorter melting duration leaves smaller periodicity. Meanwhile, we also found stripes on the surface of sapphire with much lower threshold than previously reported values. The results can benefit advanced optoelectronic device fabrication and fundamental research

Irisin protects macrophages from oxidized low density lipoprotein-induced apoptosis by inhibiting the endoplasmic reticulum stress pathway

Irisin is a newly discovered myokine which can relieve metabolic disorders and resist atherosclerosis. The effects of irisin on ox-LDL-induced macrophage apoptosis and endoplasmic reticulum stress-related pathways were observed in vitro. RAW264.7 macrophages were cultured in vitro and pretreated with irisin at 20, 40 and 80 ng/ml for 30 min, followed by culture with 100 mg/L ox-LDL and 5 mg/L tunicamycin (TM) for 12 h. The cell viability and apoptosis were detected by MTT assay and annexin V-FITC double staining. The nuclear translocation of activating transcription factor 6 (ATF6) was detected by immunofluorescence assay. Western blot was used to detect the expressions of p-PERK, p-eIF2α, C/EBP homologous protein (CHOP) and Bcl-2. Irisin reduced lipid accumulation in macrophages in a concentration-dependent pattern and significantly inhibited apoptosis induced by ox-LDL and TM. Compared with ox-LDL and TM groups, the expressions of CHOP, p-PERK and p-eIF2α in the irisin group significantly decreased, the translocation of ATF6 from cytoplasm to nucleus was significantly weakened, and Bcl-2 expression significantly increased. Irisin can alleviate the apoptosis of macrophages induced by ox-LDL, which may be achieved by inhibiting the PERK/eIF2α/CHOP and ATF6/CHOP endoplasmic reticulum stress signaling pathways. Keywords: Irisin, Endoplasmic reticulum stress, Macrophage, Apoptosi

Batf3-dependent CD8α+ Dendritic Cells Aggravates Atherosclerosis via Th1 Cell Induction and Enhanced CCL5 Expression in Plaque Macrophages

Dendritic cells (DCs) play an important role in controlling T cell-mediated adaptive immunity in atherogenesis. However, the role of the basic leucine zipper transcription factor, ATF-like 3 (Batf3)-dependent CD8α+ DC subset in atherogenesis remains unclear. Here we show that Batf3−/−Apoe−/− mice, lacking CD8α+ DCs, exhibited a significant reduction in atherogenesis and T help 1 (Th1) cells compared with Apoe−/− controls. Then, we found that CD8α+ DCs preferentially induce Th1 cells via secreting interleukin-12 (IL-12), and that the expression of interferon-gamma (IFN-γ)or chemokine (C-C motif) ligand 5 (CCL5) in aorta were significantly decreased in Batf3−/−Apoe−/− mice. We further demonstrated that macrophages were the major CCL5-expressing cells in the plaque, which was significantly reduced in Batf3−/−Apoe−/− mice. Furthermore, we found CCL5 expression in macrophages was promoted by IFN-γ. Finally, we showed that Batf3−/−Apoe−/− mice displayed decreased infiltration of leukocytes in the plaque. Thus, CD8α+ DCs aggravated atherosclerosis, likely by inducing Th1 cell response, which promoted CCL5 expression in macrophages and increased infiltration of leukocytes and lesion inflammation

Factrors and facts in Hungarian HIV/AIDS epidemic, 1985-2000

In Hungary among others there were some special factors, which shaped the outcome of HIV/AIDS epidemic. (1) In the early period of pandemic the “iron curtain” delayed and limited the importation of HIV to Hungary. (2) In 1985, at the time of detection of first HIV infected persons the etiological diagnostic tools were already commercially available and laboratory facilities have been created immediately for HIV antibody tests in networks of blood banks, public health and venereological services. (3) Laboratory facilities together with introduced health regulations resulted in (a) elimination of possibility of nosocomial HIV transmission by blood, blood products and organ transplantation; (b) efficient case finding and contact tracing in population groups potentially playing a significant role in spreading of infection; (c) opportunities for voluntary HIV testing free of charge. (4) Broad scale education and information activities have been developed from the beginning by governmental and non-governmental organizations alike. (5) Parenteral drug abuse did not play a role in spreading of HIV, so far. The above factors resulted in a slowly developing moderate epidemic. The facts are as follows. By the end of 2000 altogether 879 HIV positive (666 male, 100 female and 113 anonymous) persons have been notified, 377 (344 male and 33 female) of whom showed already the characteristic features of AIDS and 229 died. 29% of registered HIV positive persons have been foreigners originating from 56 countries. The cumulative incidence rate of AIDS was 38 per million population. 73% of Hungarian HIV positive persons and 72% of patients with AIDS belonged to transmission group of men having sex with men. The age of HIV positive persons at the time of detection was between 20 and 49 years in 81% and 72% of them resided in or around Budapest

Niacin Inhibits Vascular Inflammation via Downregulating Nuclear Transcription Factor-κB Signaling Pathway

The study aimed to investigate the effect of niacin on vascular inflammatory lesions in vivo and in vitro as well as its lipid-regulating mechanism. In vivo study revealed that niacin downregulated the levels of inflammatory factors (IL-6 and TNF-α) in plasma, suppressed protein expression of CD68 and NF-κB p65 in arterial wall, and attenuated oxidative stress in guinea pigs that have been fed high fat diet. In vitro study further confirmed that niacin decreased the secretion of IL-6 and TNF-α and inhibited NF-κB p65 and notch1 protein expression in oxLDL-stimulated HUVECs and THP-1 macrophages. Moreover, niacin attenuated oxLDL-induced apoptosis of HUVECs as well. In addition, niacin significantly lessened lipid deposition in arterial wall, increased HDL-C and apoA levels and decreased TG and non-HDL-C levels in plasma, and upregulated the mRNA amount of cholesterol 7α-hydroxylase A1 in liver of guinea pigs. These data suggest for the first time that niacin inhibits vascular inflammation in vivo and in vitro via downregulating NF-κB signaling pathway. Furthermore, niacin also modulates plasma lipid by upregulating the expression of factors involved in the process of reverse cholesterol transport