Fibrate Family Research Articles

Homotopy Fibrations with a Section After Looping

We analyze a general family of fibrations which, after looping, have sections. Methods are developed to determine the homotopy type of the fibre and the homotopy classes of the map from the fibre to the base. The methods are driven by applications to two-cones, Poincaré Duality complexes, the connected sum operation, and polyhedral products.

Dihedral monodromy and Xiao fibrations

We construct three new families of fibrations $\pi : S \to B$ where $S$ is an algebraic complex surface and $B$ a curve that violate Xiao's conjecture relating the relative irregularity and the genus of the general fiber. The fibers of $\pi$ are certain \'etale cyclic covers of hyperelliptic curves that give coverings of $P^1$ with dihedral monodromy. As an application, we also show the existence of big and nef effective divisors in the Brill-Noether range.

Indicaciones de la combinación de pravastatina y fenofibrato según el nivel de riesgo cardiovascular. Situaciones clínicas habituales

In diabetes, metabolic syndrome, some types of familial dyslipidemia, ischemic pathology of atheromatous origin and renal failure, the presence of mixed dyslipidemia is common. In other words, there is an excess of cholesterol and triglycerides, associated or not with HDL-c deficiency. These clinical conditions are associated with high to very high cardiovascular risk. It is appropriate when treating these conditions to achieve an overall control of lipid metabolism abnormalities, in terms of excess cholesterol carried by atherogenic lipoproteins (LDL-c and non-HDL-c) and triglyceride excess and deficit of HDL-c. To achieve this overall control is necessary to correct the potential causes of secondary dyslipidemia, improve lifestyle habits and use a drug from the statin family, and it is often necessary to combine a drug from the fibrate family. This combination has been shown to be eff ective and safe in the overall control of dyslipidemia and the cardiovascular risk prevention in patients at high risk. This combination has been shown to have a favorable eff ect in the population with diabetes and microangiopathy, both in the retina and in the glomerulus. For patients with moderate renal failure, the use of fibrates is controversial, and there are marked disagreements between the recommendations issued by various organizations and expert consensus groups.

Universal bivariant algebraic K-theories

To any admissible category of algebras and a family of fibrations on it a universal bivariant excisive homotopy invariant algebraic K-theory is associated. Also, Morita invariant and stable universal bivariant K-theories are studied. We introduce an additive category of correspondencies for non-unital algebras and study the problem of when stable bivariant K-groups can be computed by means of correspondences.

Biomolecular Chemistry of Isopropyl Fibrates

Isopropyl 2-[4-(4-chlorobenzoyl)-phenoxy]-2-methylpropanoic acid and isopropyl 2-(4-chlorophenoxy)-2-methylpropanoate, also known as fenofibrate and isopropyl (iPr) clofibrate, are hypolipidemic agents of the fibrate family. In a previously reported triclinic structure of fenofibrate (polymorph I), the methyl groups of the iPr moiety are located symmetrically about the carboxylate group. We report a new monoclinic form (polymorph II) of fenofibrate and a first structural description of iPr clofibrate, and in these the methyl groups are placed asymmetrically about the carboxylate group. In particular, the dihedral (torsion) angle between the hydrogen atom on the secondary C and the C atom of the carboxyl group makes a 2.74° angle about the ester O···C bond in the symmetric fenofibrate structure of polymorph I, whereas the same dihedral angle is 45.94° in polymorph II and -30.9° in the crystal structure of iPr clofibrate. Gas-phase density functional theory (DFT) geometry minimizations of fenofibrate and iPr clofibrate result in lowest energy conformations for both molecules with a value of about ±30° for this same angle between the OC-O-C plane and the C-H bond of the iPr group. A survey of crystal structures containing an iPr ester group reveals that the asymmetric conformation is predominant. Although the hydrogen atom on the secondary C atom of the iPr group is located at a comparable distance from the carbonyl oxygen in the symmetric and asymmetric fenofibrate (2.52 and 2.28 Å) and the iPr clofibrate (2.36 Å) structures, this hydrogen atom participates in a puckered five-membered ring arrangement in the latter two that is unlike the planar arrangement found in symmetric fenofibrate (polymorph I). Polar molecular surface area values indicate fenofibrate and iPr clofibrate are less able to act as acceptors of hydrogen bonds than their corresponding acid derivatives. Surface area calculations show that dynamic polar molecular surface area values of the iPr esters of the fibrates are lower than those of their acids, implying that the fibrates have better membrane permeability and a higher absorbability and hence are better prodrugs when these agents need to be orally administered.

PPARαin Obesity: Sex Difference and Estrogen Involvement

Peroxisome proliferator-activated receptor α (PPARα) is a member of the steroid hormone receptor superfamily and is well known to act as the molecular target for lipid-lowering drugs of the fibrate family. At the molecular level, PPARα regulates the transcription of a number of genes critical for lipid and lipoprotein metabolism. PPARα activators are further shown to reduce body weight gain and adiposity, at least in part, due to the increase of hepatic fatty acid oxidation and the decrease in levels of circulating triglycerides responsible for adipose cell hypertrophy and hyperplasia. However, these effects of the PPARα ligand fenofibrate on obesity are regulated with sexual dimorphism and seem to be influenced by the presence of functioning ovaries, suggesting the involvement of ovarian steroids in the control of obesity by PPARα. In female ovariectomized mice, 17β-estradiol inhibits the actions of fenofibrate on obesity through its suppressive effects on the expression of PPARα target genes, and these processes may be mediated by inhibiting the coactivator recruitment of PPARα. Thus, it is likely that PPARα functions on obesity may be enhanced in estrogen-deficient states.

REAL ANALYTIC GERMS $f \bar{g}$ AND OPEN-BOOK DECOMPOSITIONS OF THE 3-SPHERE

Let f,g: (C2,0) → (C,0) be two holomorphic germs with isolated singularities and no common branches and let Lf, [Formula: see text] be their links. We prove that the real analytic germ [Formula: see text] has an isolated singularity at 0 if and only if the link Lf ∪ -Lg is fibred. This was conjectured by Rudolph in [14]. If this condition holds, then the underlying Milnor fibration is an open-book fibration of the link Lf ∪ -Lg which coincides with [Formula: see text] in a tubular neighbourhood of this link. This enables one to realize a large family of fibrations of plumbing links in S3 as the Milnor fibrations of some real analytic germs [Formula: see text].

Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells.

A large body of data gathered over the past couple of years has identified the peroxisome proliferator-activated receptors (PPAR) alpha, gamma, and beta/delta as transcription factors exerting modulatory actions in vascular cells. PPARs, which belong to the nuclear receptor family of ligand-activated transcription factors, were originally described as gene regulators of various metabolic pathways. Although the PPARalpha, gamma, and beta/delta subtypes are approximately 60% to 80% homologous in their ligand- and DNA-binding domains, significant differences in ligand and target gene specificities are observed. PPARalpha is activated by polyunsaturated fatty acids and oxidized derivatives and by lipid-modifying drugs of the fibrate family, including fenofibrate or gemfibrozil. PPARalpha controls expression of genes implicated in lipid metabolism. PPARgamma, in contrast, is a key regulator of glucose homeostasis and adipogenesis. Ligands of PPARgamma include naturally occurring FA derivatives, such as hydroxyoctadecadienoic acids (HODEs), prostaglandin derivatives such as 15-deoxyDelta12,14-prostaglandin J2, and glitazones, insulin-sensitizing drugs presently used to treat patients with type 2 diabetes. Ligands for PPARbeta/delta are polyunsaturated fatty acids, prostaglandins, and synthetic compounds, some of which are presently in clinical development. PPARbeta/delta stimulates fatty acid oxidation predominantly acting in muscle. All PPARs are expressed in vascular cells, where they exhibit antiinflammatory and antiatherogenic properties. In addition, studies in various animal models as well as clinical data suggest that PPARalpha and PPARgamma activators can modulate atherogenesis in vivo. At present, no data are available relating to possible effects of PPARbeta/delta agonists on atherogenesis. Given the widespread use of PPARalpha and PPARgamma agonists in patients at high risk for cardiovascular disease, the understanding of their function in the vasculature is not only of basic interest but also has important clinical implications. This review will focus on the role of PPARs in the vasculature and summarize the present understanding of their effects on atherogenesis and its cardiovascular complications.

Regulation of the peroxisomal β-oxidation-dependent pathway by peroxisome proliferator-activated receptor α and kinases

The first PPAR (peroxisome proliferator-activated receptor) was cloned in 1990 by Issemann and Green ( Nature 347:645–650). This nuclear receptor was so named since it is activated by peroxisome proliferators including several drugs of the fibrate family, plasticizers, and herbicides. This receptor belongs to the steroid receptor superfamily. After activation by a specific ligand, it binds to a DNA response element, PPRE (peroxisome proliferator response element), which is a DR-1 direct repeat of the consensus sequence TGACCT × TGACCT. This mechanism leads to the transcriptional activation of target genes (Motojima et al., J Biol Chem 273:16710–16714, 1998). After the first discovery, several isoforms were characterized in most of the vertebrates investigated. PPARα, activated by hypolipidemic agents of the fibrate family or by leukotrienes; regulates lipid metabolism as well as the detoxifying enzyme-encoding genes. PPARβ/δ, which is not very well known yet, appears to be more specifically activated by fatty acids. PPARγ (subisoforms 1, 2, 3) is activated by the prostaglandin PGJ2 or by antidiabetic thiazolidinediones (Vamecq and Latruffe, Lancet 354:411–418, 1999). This latter isoform is involved in adipogenesis. The level of PPAR expression is largely dependent on the tissue type. PPARα is mainly expressed in liver and kidney, while PPARβ/δ is almost constitutively expressed. In contrast, PPARγ is largely expressed in white adipose tissue. PPAR is a transcriptional factor that requires other nuclear proteins in order to function, i.e. RXRα (9- cis-retinoic acid receptor α) in all cases in addition to other regulatory proteins. Peroxisomes are specific organelles for very long-chain and polyunsaturated fatty acid catabolism. From our results and those of others, the inventory of the role of PPARα in the regulation of peroxisomal fatty acid β-oxidation is presented. In relation to this, we showed that PPARα activates peroxisomal β-oxidation-encoding genes such as acyl-CoA oxidase, multifunctional protein, and thiolase (Bardot et al., FEBS Lett 360:183–186, 1995). Moreover, rat liver PPARα regulatory activity is dependent on its phosphorylated state (Passilly et al., Biochem Pharmacol 58:1001–1008, 1999). On the other hand, some signal transduction pathways such as protein kinase C are modified by peroxisome proliferators that increase the phosphorylation level of some specific proteins (Passilly et al. Eur J Biochem 230:316–321, 1995). From all these findings, PPARα and kinases appear to play an important role in lipid homeostasis.

Relationship Between Signal Transduction and PPARα-Regulated Genes of Lipid Metabolism in Rat Hepatic-Derived Fao Cells

The goal of this study was to characterize phosphorylated proteins and to evaluate the changes in their phosphorylation level under the influence of a peroxisome proliferator (PP) with hypolipidemic activity of the fibrate family. The incubation of rat hepatic derived Fao cells with ciprofibrate leads to an overphosphorylation of proteins, especially one of 85 kDa, indicating that kinase (or phosphatase) activities are modified. Moreover, immunoprecipitation of 32P-labeled cell lysates shows that the nuclear receptor, PP-activated receptor, alpha isoform, can exist in a phosphorylated form, and its phosphorylation is increased by ciprofibrate. This study shows that PP acts at different steps of cell signaling. These steps can modulate gene expression of enzymes involved in fatty acid metabolism and lipid homeostasis, as well as in detoxication processes.

Carcinogenic aspect of xenobiotic molecules belonging to the peroxisome proliferator family.

It is known that a short-term exposure of rat, mice or incubation of hepatic cells with fibrate molecules leads to increase in peroxisome number and cell hyperplasia. Further, long-term incubation of cells (at least a year) show transformed characteristics with foci and nodules. To explain the hepatocarcinogenic effect of peroxisome proliferators in rodents we studied the effect of peroxisome proliferators on rat liver oncogenes expression. Earlier, we reported an increase in liver and kidney mRNA level of c-myc and N-myc. Since several metabolic genes are activated by PPAR (peroxisome proliferators activated receptor) through a PPRE (peroxisome proliferator response element), we suggest the involvment of PPAR in oncogene activation, because of the presence of PPRE in the N-myc 5'-upstream region. We showed by flow cytometric analysis that ciprofibrate increased the size of rat Fao derived cell line and the activity of palmitoyl CoA oxidase, a peroxisome proliferation enzyme marker for studying peroxisome proliferation was increased. The above effects which can contribute to hepatocarcinogenesis seem to be restricted to rat and mice, which show strong response to peroxisome proliferators. Indeed, no changes are observed in weak responsive species such as humans (using hepatic derived cell lines) and guinea pig. These data provide arguments for the non-carcinogenic effect of this xenobiotic class in human especially when sensitive, or normal individuals are exposed either to hypolipidaemic agents of the fibrate family.

Preparation of a dansylated fibrate, a new fluorescent tool to study peroxisome proliferation. Effect on hepatic-derived cell lines

The synthesis of a dansylated fibrate (DNS-X) has been performed in order to identify the cellular affinity sites of peroxisome proliferators and to establish the subcellular localization of such molecules. DNS-X has been obtained by coupling the dansyl chloride with the amine resulting from the bezafibrate alkaline hydrolysis. The purified DNS-X has been further characterized by spectrum analysis (UV-Vis, fluorescence, [ 1H]/[ 3C]-NMR and mass). At 250 μM and incubated for 48 h with the rat hepatic derived cells (Fao cells). DNS-X stimulates 12-fold the palmitoyl-CoA oxidase, a peroxisome proliferation marker enzyme. This increase is comparable to the one obtained with well known peroxisome proliferators such as bezafibrate or ciprofibrate. The stimulation by DNS-X is specific for the overall molecule since neither the dansyl chloride, the amine, nor the precursors of DNS-X are active. The increase of palmitoyl-CoA oxidase activity is correlated with the increase of the enzyme amount as shown by immunoblotting. In agreement with the species-specificity of the fibrate neither DNS-X, bezafibrate nor ciprofibrate significantly increase palmitoyl-CoA oxidase activity and the enzyme amount in human hepatic-derived cells, HepG2. This work shows that the dansylated fibrate is a new fluorescent tool to study the subcellular localization and identification of high affinity binding sites, then further on, to elucidate the peroxisome proliferation mechanism and the action of hypolipidaemic agents of the fibrate family.

Smooth families of fibrations and analytic selections of polynomial hulls

Constructed are strictly increasing smooth families Σt ⊆ ∂D × C2, t ∈ [0, 1], of fibrations over the unit circle with strongly pseudoconvex fibers all diffeomorphic to the ball such that there is no analytic selection of the polynomial hull of Σ0 and which end at the product fibration . In particular these examples show that the continuity method for describing the polynomial hull of a fibration over ∂D fails even if the complex geometry of the fibers is relatively simple.

Transcriptional induction of the fatty acid binding protein gene in mouse liver by bezafibrate

The mechanism by which hypolipidemic peroxisome proliferators of the fibrate family induce the liver fatty acid binding protein in liver of rodents is unknown. In order to delineate the level at which this protein is induced, the transcriptional activity of the specific gene encoding for liver fatty acid binding protein was measured in isolated hepatocyte nuclei obtained from male Swiss mice daily force-fed during 7 days with 400 mg/kg body weight bezafibrate. This treatment induced a 4-fold increase in the liver fatty acid binding protein transcription rate. Liver fatty acid binding protein mRNA level, measured by Northern blot analysis and cytosolic content of this protein, analyzed by immunoblotting, increased concurrently. From these results we conclude that the increase in the cytosolic liver fatty acid binding protein level by bezafibrate is due to an enhancement of the transcription rate of the liver fatty acid binding protein gene. Whether the transcriptional effect is mediated by peroxisome proliferator-receptor remains to be elucidated.

Great sphere fibrations of manifolds

Abstract : There are three questions that guide our study: (1) given two fibrations are they topologically equivalent, (2) is it possible to deform one fibration to another through a one parameter family of fibrations, and (3) what is the homotopy type of the space of all fibrations? We address these questions for great circle fibrations of odd dimensional round spheres and arbitrary great k-sphere fibrations.

A mod 𝑝 Whitehead theorem

A mod p p Whitehead theorem is proved which is the relative version of a basic result of localization theory. It is applied to give a family of fibrations which are also cofibrations.