The nuclear receptors LXR␣ and LXR have been implicated in the control of cholesterol and fatty acid metabolism in multiple cell types. Activation of these receptors stimulates cholesterol efflux in macrophages, promotes bile acid synthesis in liver, and inhibits intestinal cholesterol absorption, actions that would collectively be expected to reduce atherosclerotic risk. However, synthetic LXR ligands have also been shown to induce lipogenesis and hypertriglyceridemia in mice, raising questions as to the net effects of these compounds on the development of cardiovascular disease. We demonstrate here that the nonsteroidal LXR agonist GW3965 has potent antiatherogenic activity in two different murine models. In LDLR ؊͞؊ mice, GW3965 reduced lesion area by 53% in males and 34% in females. A similar reduction of 47% was observed in male apoE ؊͞؊ mice. Long-term (12-week) treatment with LXR agonist had differential effects on plasma lipid profiles in LDLR ؊͞؊ and apoE ؊͞؊ mice. GW3965 induced expression of ATP-binding cassettes A1 and G1 in modified low-density lipoprotein-loaded macrophages in vitro as well as in the aortas of hyperlipidemic mice, suggesting that direct actions of LXR ligands on vascular gene expression are likely to contribute to their antiatherogenic effects. These observations provide direct evidence for an atheroprotective effect of LXR agonists and support their further evaluation as potential modulators of human cardiovascular disease.R ecent work has identified the nuclear receptors LXR␣ and LXR as central regulators of lipid homeostasis. The physiologic ligands for these receptors are likely to be specific intermediates in the cholesterol biosynthetic pathway such as 24(S),25-epoxycholesterol (1-3). LXR␣ is expressed primarily in liver, intestine, adipose tissue, and macrophages, whereas LXR is expressed in many cell types (4). In peripheral cells such as macrophages, LXRs seem to coordinate a physiologic response to cellular cholesterol loading. LXRs directly control transcription of several genes involved in the cholesterol efflux pathway, including ATP-binding cassette (ABC) A1 (5-8), ABCG1 (9), and apolipoprotein E (apoE) (10). In the intestine, ligand activation of LXR͞RXR heterodimers dramatically reduces dietary cholesterol absorption, an effect postulated to be mediated by ABCA1 (6).In the liver, LXRs seem to regulate both cholesterol and fatty acid metabolism. Mice carrying a targeted disruption of the Lxr␣ gene fail to induce transcription of the gene encoding cholesterol 7␣-hydroxylase (CYP7A1) in response to dietary cholesterol, implicating LXRs in the control of bile acid synthesis (11). Mice lacking LXR␣ were also observed to be deficient in expression of fatty acid synthase, steroyl-coA desaturase 1, acyl-coA carboxylase, and sterol regulatory element binding protein-1, suggesting an additional role in lipogenesis. This hypothesis was supported by the subsequent demonstration that the synthetic LXR ligand T1317 induces expression of lipogenic genes and raises plasma trigly...
Although a wide range of risk factors for coronary heart disease have been identified from population studies, these measures, singly or in combination, are insufficiently powerful to provide a reliable, noninvasive diagnosis of the presence of coronary heart disease. Here we show that pattern-recognition techniques applied to proton nuclear magnetic resonance (1H-NMR) spectra of human serum can correctly diagnose not only the presence, but also the severity, of coronary heart disease. Application of supervised partial least squares-discriminant analysis to orthogonal signal-corrected data sets allows >90% of subjects with stenosis of all three major coronary vessels to be distinguished from subjects with angiographically normal coronary arteries, with a specificity of >90%. Our studies show for the first time a technique capable of providing an accurate, noninvasive and rapid diagnosis of coronary heart disease that can be used clinically, either in population screening or to allow effective targeting of treatments such as statins.
Although a wide range of risk factors for coronary heart disease have been identified from population studies, these measures, singly or in combination, are insufficiently powerful to provide a reliable, noninvasive diagnosis of the presence of coronary heart disease. Here we show that pattern-recognition techniques applied to proton nuclear magnetic resonance (1H-NMR) spectra of human serum can correctly diagnose not only the presence, but also the severity, of coronary heart disease. Application of supervised partial least squares-discriminant analysis to orthogonal signal-corrected data sets allows >90% of subjects with stenosis of all three major coronary vessels to be distinguished from subjects with angiographically normal coronary arteries, with a specificity of >90%. Our studies show for the first time a technique capable of providing an accurate, noninvasive and rapid diagnosis of coronary heart disease that can be used clinically, either in population screening or to allow effective targeting of treatments such as statins.
Apolipoprotein E (apoE) is a 34-kDa glycoprotein involved in lipoprotein transport through interaction with the low-density lipoprotein receptor and related receptors. Recently, it has become clear that apoE binding to its receptors plays a role both in development and in control of the immune system. In this study, we show that apoE modulates the rate of uptake of apoptotic cells by macrophages. In vitro, apoE-deficient macrophages ingest less apoptotic thymocytes (but not latex beads) than wild-type macrophages, and this defect can be corrected by addition of exogenous apoE protein. In vivo, the number of dying macrophages is increased in a range of tissues, including lung and brain. Possibly in response to the larger numbers of persistent apoptotic bodies, the number of live macrophages in these tissues are also increased compared with those of wild-type control mice. In addition to the significant changes in macrophage population dynamics we observed, levels of the proinflammatory cytokine TNF-α and the positive acute phase reactant fibrinogen are also elevated in the livers from apoE-deficient mice. In contrast, neither deletion of the gene encoding the LDL receptor nor cholesterol feeding of wild-type mice affected either the number of apoptotic bodies or the number of live macrophages. We conclude that apoE deficiency results in impaired clearance of apoptotic cell remnants and a functionally relevant systemic proinflammatory condition in mice, independent of its role in lipoprotein metabolism. Any similar reduction of apoE activity in humans may contribute to the pathogenesis of a wide range of chronic diseases including atherosclerosis, dementia, and osteoporosis.
Background: A major determinant of the risk of myocardial infarction is the stability of the atherosclerotic plaque. Macrophage-rich plaques are more vulnerable to rupture, since macrophages excrete an excess of matrix-degrading enzymes over their inhibitors, reducing collagen content and thinning the fibrous cap. Several genetic studies have shown that disruption of signalling by the chemokine monocyte chemoattractant protein 1 reduced the lipid lesion area and macrophage accumulation in the vessel wall. Methods: We have tested whether a similar reduction in macrophage accumulation could be achieved pharmacologically by treating apolipoprotein-E-deficient mice with the chemokine inhibitor NR58-3.14.3. Results: Mice treated for various periods of time (from several days to 6 months) with NR58-3.14.3 (approximately 30 mg/kg/day) consistently had 30–40% fewer macrophages in vascular lesions, compared with mice treated with the inactive control NR58-3.14.4 or PBS vehicle. Similarly, cleaved collagen staining was lower in mice treated for up to 7 days, although this effect was not maintained when treatment time was extended to 12 weeks. The vascular lipid lesion area was unaffected by treatment, but total collagen I staining and smooth muscle cell number were both increased, suggesting that a shift to a more stable plaque phenotype had been achieved. Conclusions: Strategies, such as chemokine inhibition, to attenuate macrophage accumulation may therefore be useful to promote stabilization of atherosclerotic plaques.
Four novel, disubstituted diaminopteridines have been identified which antagonize the uptake of a folate precursor (para-aminobenzoic acid) by rat-derived Pneumocystis carinii maintained in short-term axenic culture at concentrations ranging from 4.5 to 26 microM. The compounds were at least 10 to 100 times more active than trimethoprim in this assay. None of these entities exhibited toxicity to mammalian cell lines at < 100 microM. The same structures also caused significant inhibition of Toxoplasma gondii tachyzoite replication within Madin-Darby bovine kidney cells at concentrations ranging from 0.1 to 10 microM. Three of the structures (GR92754, AH10639, and AH2504) were at least an order of magnitude more potent than the standard anti-T. gondii agent, pyrimethamine. All three entities were also significantly more potent and selective than pyrimethamine as inhibitors of T. gondii dihydrofolate reductase (DHFR), with 50% inhibitory concentrations within the range of 0.018 to 0.033 microM. One of these compounds, 6,7-dibutyl-2,4-diaminopteridine (GR92754), was also a potent and selective inhibitor of P. carinii DHFR (50% inhibitory concentration, 0.082 microM). GR92754 is the first DHFR inhibitor described that exhibits greater potency, selectivity, and intracellular activity against both organisms than any of the DHFR agents used clinically, namely, trimethoprim, pyrimethamine, and trimetrexate. This information could provide the starting point for examination of the pharmacokinetic and therapeutic potential of GR92754 and related chemical entities with animal models.
Toll-like receptor-4 (TLR4) signaling augments chemokine-induced neutrophil migration by modulating cell surface expression of chemokine receptors Jie Fan & Asrar B. Malik Nat. Med. 9, 315-321 (2003). Fig. 1d: the 'MIP-2' label over lane 4 should be over lane 5. The correct figure is below. We regret the errors.
The dividing line between essential physiological inflammatory processes and excessive pathological inflammation is often very thin - in some circumstances, indeed, it may be non-existent. Devising anti-inflammatory medications that effectively target only the pathological component therefore remains a central challenge for the pharmaceutical industry. At present, the general rule is that the more powerful the anti-inflammatory effect of a drug, the greater the side-effects that accompany it. Steroids, for example, are potent anti-inflammatory medications, but they have a diverse array of side effects that substantially limit their use. Since chemokines play a central role in regulating the immune system, and in particular, the trafficking of leukocytes, inhibiting their action may represent a powerful new therapeutic strategy for treating diseases with an inflammatory component. However, this potential will only be realized if it is possible to interfere with chemokine signaling networks, without inducing unacceptable side effects. Although very little, direct human toxicology has been carried out using chemokine inhibitors, there is now a sufficient body of indirect and circumstantial evidence (for example, from genetically modified mice and from animal model studies using chemokine inhibitors) to allow a tentative assessment of the biological impact of chemokine inhibition. The purpose of this review is to outline the available data and to speculate on the likely toxicological profile resulting from chemokine inhibition. The tentative conclusion is that anti-inflammatory therapy achieved through chemokine inhibition may have fewer side effects than originally expected, even when the actions of multiple chemokines are inhibited simultaneously.
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