PPARα, β/δ, and γ regulate genes involved in the control of lipid metabolism and inflammation and are expressed in all major cell types of atherosclerotic lesions. In vitro studies have suggested that PPARs exert antiatherogenic effects by inhibiting the expression of proinflammatory genes and enhancing cholesterol efflux via activation of the liver X receptor-ABCA1 (LXR-ABCA1) pathway. To investigate the potential importance of these activities in vivo, we performed a systematic analysis of the effects of PPARα, β, and γ agonists on foam-cell formation and atherosclerosis in male LDL receptor-deficient (LDLR -/-) mice. Like the PPARγ agonist, a PPARα-specific agonist strongly inhibited atherosclerosis, whereas a PPARβ-specific agonist failed to inhibit lesion formation. In concert with their effects on atherosclerosis, PPARα and PPARγ agonists, but not the PPARβ agonist, inhibited the formation of macrophage foam cells in the peritoneal cavity. Unexpectedly, PPARα and PPARγ agonists inhibited foam-cell formation in vivo through distinct ABCA1-independent pathways. While inhibition of foam-cell formation by PPARα required LXRs, activation of PPARγ reduced cholesterol esterification, induced expression of ABCG1, and stimulated HDL-dependent cholesterol efflux in an LXR-independent manner. In concert, these findings reveal receptor-specific mechanisms by which PPARs influence macrophage cholesterol homeostasis. In the future, these mechanisms may be exploited pharmacologically to inhibit the development of atherosclerosis.
Radio frequency identification application has significant process-orientated and technological implications. It is feasible and economically justifiable to incorporate RFID into blood centre processes.
Objective-The purpose of this research was to determine how dietary bile acids repress hepatic expression of paraoxonase 1 (PON1). Methods and Results-C57BL/6 mice and C3H/HeJ mice, having different susceptibilities to atherosclerosis, were fed a chow diet and an atherogenic diet containing taurocholate. Compared with the more atherosclerosis-susceptible C57BL/6 mice, C3H/HeJ mice display resistance to dietary bile acid repression of hepatic PON1 mRNA and decreased high-density lipoprotein cholesterol. Whereas knockout of toll receptor 4 did not affect response to taurocholate, deletion of either FXR or FGFR4 blocked taurocholate repression of PON1 and CYP7A1. FGF19, an activator of FGFR4 expressed in human ileum, decreased expression of both PON1 and CYP7A1 expression by human hepatoma cells. In all of the mice studied, dietary taurocholate increased ileal expression of FGF15, a FXR-inducible murine homologue of human FGF19. Conclusions-Hepatic PON1 and CYP7A1 mRNA expression is repressed by bile acids via FXR-mediated induction of FGF15. Thus, the inability of C3H/HeJ mice to display taurocholate repression of PON1 and CYP7A1 mRNAs was not because of a lack of induction of FGF15 but rather signaling events distal to FGF15-FGFR4 association. M ultiple case-controlled studies of humans show an inverse relationship among the plasma activity of paraoxonase 1 (PON1), the formation of atherosclerotic lesions, and myocardial infarction. [1][2][3][4][5][6] Thus, plasma levels of PON1 accurately predict susceptibility to atherosclerosis.PON1 is mainly expressed in the liver 7 and displays the unusual characteristic of being secreted with an intact N-terminal signal sequence. 8 PON1 exhibits multiple enzyme activities including acting as an organophosphate esterase, a carboxyl esterase, 9,10 a lactonase, 11,12 and a phospholipase A2. 13,14 The latter activity has been proposed to play an important role in inactivating the proatherogenic inflammatory lipids produced by the oxidative modification of lowdensity lipoprotein. 15 Most of the PON1 present in plasma is associated with high-density lipoprotein (HDL), which may explain the well-established atheroprotective effect of HDL. 13,16,17 The antiinflammatory properties of HDL are dependent, at least in part, on the presence of PON1. 13 Dissociation of PON1 from HDL causes the HDL particle to become atherogenic. 13 Studies using inbred strains of mice showed that a cholic acid-containing atherogenic diet reduced the hepatic expression of both PON1 and CYP7A1 mRNAs and plasma HDL cholesterol levels in atherosclerosis-susceptible C57BL/6 mice but not in atherosclerosis-resistant C3H/HeJ mice. 18 Additional analysis of a subset of recombinant inbred strains derived from the B6 and C3H parental strains showed that the ability of the cholic acid-containing atherogenic diet to decrease hepatic PON1 mRNA expression segregated with aortic lesion development. 18 In a similar subset of recombinant progeny from B6 and C3H parental strains, HDL levels were linked to 3 individual gene...
Constitutive expression of a cholesterol-7a-hydroxylase (CYP7A1) transgene in LDL receptor-deficient mice blocked the ability of a cholesterol-enriched diet to increase plasma levels of apolipoprotein B-containing lipoproteins. LDL receptor-deficient mice expressing the CYP7A1 transgene exhibited complete resistance to diet-induced hypercholesterolemia and to the accumulation of cholesterol in the liver. Hepatic mRNA expression of liver X receptorinducible ABCG5 and ABCG8 was decreased in CYP7A1 transgenic, LDL receptor-deficient mice fed a cholesterolenriched diet. Thus, increased biliary cholesterol excretion could not account for the maintenance of cholesterol homeostasis. CYP7A1 transgenic, LDL receptor-deficient mice fed the cholesterol-enriched diet exhibited decreased jejunal Niemann-Pick C1-Like 1 protein (NPC1L1) mRNA expression, an important mediator of intestinal cholesterol absorption. A taurocholate-enriched diet also decreased NPC1L1 mRNA expression in a farnesoid X receptor-independent manner. Reduced expression of NPC1L1 mRNA was associated with decreased cholesterol absorption (z20%; P , 0.05) exhibited by CYP7A1 transgenic LDL receptor-deficient mice fed the cholesterol-enriched diet. The combined data show that enhanced expression of CYP7A1 is an effective means to prevent the accumulation of cholesterol in the liver and of atherogenic apolipoprotein B-containing lipoproteins in plasma.-Ratliff, E. P., A. Gutierrez, and R. A. Davis. Hepatic expression of cholesterol-7a-hydroxylase (CYP7A1), the enzyme regulating the conversion of cholesterol to bile acids, plays a crucial role in eliminating excess cholesterol from the body (reviewed in 1). Studies in rats show that biliary excretion of bile acids and cholesterol accounts for z85% of the cholesterol eliminated from the body (2). The ability of the cholesterol-to-bile acid pathway to vary in parallel with changes in the endogenous cholesterol pool plays an important role in maintaining whole body cholesterol homeostasis (3, 4). In rodents such as mice and rats, sterol-mediated activation of the nuclear liver X receptor (LXR) increases CYP7A1 gene expression and, thus, provides a mechanism to maintain cholesterol homeostasis (5, 6). In contrast to the rat and mouse CYP7A1 genes, the human CYP7A1 gene does not display LXRmediated enhancement of transcription (7,8).By altering hepatic expression of sterol-regulatory element binding protein (SREBP)-mediated genes, CYP7A1 has a marked influence on many processes that control lipoprotein production as well as LDL receptor-dependent removal from plasma (9, 10). Hepatic expression of CYP7A1 indirectly controls plasma LDL levels by influencing the expression of LDL receptors (11). Studies showing that the expression of CYP7A1 in nonhepatic CHO cells enhanced the expression of LDL receptors further indicate the critical role for cholesterol catabolism in maintaining cholesterol homeostasis (9). Transgenic expression of CYP7A1 in hepatoma cells (10), CHO cells (12), and macrophages (13) also acti...
Anti-HCMV treatments used in immunosuppressed patients reduce viral replication, but resistant viral strains can emerge. Moreover, these drugs do not target latently infected cells. We designed two anti-viral CRISPR/Cas9 strategies to target the UL122/123 gene, a key regulator of lytic replication and reactivation from latency. The singleplex strategy contains one gRNA to target the start codon. The multiplex strategy contains three gRNAs to excise the complete UL122/123 gene. Primary fibroblasts and U-251 MG cells were transduced with lentiviral vectors encoding Cas9 and one or three gRNAs. Both strategies induced mutations in the target gene and a concomitant reduction of immediate early (IE) protein expression in primary fibroblasts. Further detailed analysis in U-251 MG cells showed that the singleplex strategy induced 50% of indels in the viral genome, leading to a reduction in IE protein expression. The multiplex strategy excised the IE gene in 90% of all viral genomes and thus led to the inhibition of IE protein expression. Consequently, viral genome replication and late protein expression were reduced by 90%. Finally, the production of new viral particles was nearly abrogated. In conclusion, the multiplex anti-UL122/123 CRISPR/Cas9 system can target the viral genome efficiently enough to significantly prevent viral replication.
Background-There is growing interest in radio frequency identification (RFID) technology application for tracking blood products to achieve higher productivity and safety in the transfusion medicine supply chain. We have conducted a limited study to assess the temperature and biological effects of 13.56 MHz RF radiation on red blood cells (RBC) and whole blood-derived platelets (WBDP) under extreme exposure conditions.
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