Sexual Dimorphism in Circadian Physiology Is Altered in LXRα Deficient Mice.

The mammalian circadian timing system coordinates key molecular, cellular and physiological processes along the 24-h cycle. Accumulating evidence suggests that many clock-controlled processes display a sexual dimorphism. In mammals this is well exemplified by the difference between the male and female circadian patterns of glucocorticoid hormone secretion and clock gene expression.

Analysis of sterol-regulatory element-binding protein 1c target genes in mouse liver during aging and high-fat diet.

Background: The sterol regulatory element-binding protein (SREBP) 1c contributes to the transcriptional coordination of cholesterol, fatty acid, and carbohydrate metabolisms. Alterations in these processes accelerate the progression of hepatic steatosis and insulin resistance during aging and obesity.

Methods: Using an ex vivo chromatin immunoprecipitation coupled to microarray (ChIP-on-chip) technique combined with genome-wide gene expression analysis, we analyzed the transcriptomic adaptations mediated by Srebp-1c binding to gene promoters in the liver of mice fed with a low-fat diet or a high-fat diet (HFD) for either 1 or 12 months.

Effect of oxime ether incorporation in acyl indole derivatives on PPAR subtype selectivity.

Compounds that simultaneously activate peroxisome proliferator-activated receptor (PPAR) subtypes α and γ have the potential to effectively treat dyslipidemia and type 2 diabetes (T2D) in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, were expected to be overcome by using additive PPARα activity, leading to dual PPARα/γ agonists with balanced activity for both subtypes. Herein we report the discovery, synthesis, and optimization of a new series of α-ethoxyphenylpropionic acid bearing 5- or 6-substituted indoles.

Aging and obesity induce distinct gene expression adaptation in the liver of C57BL/6J mice.

Background: Aging and obesity induce complex transcriptomic changes in the liver, promoting the development of insulin resistance and type 2 diabetes. In spite of an increasing amount of studies on the role of aging and nutrient excess in metabolic disorders, the specific molecular events leading to insulin resistance are still poorly understood.

Methods: This study presents a comparative analysis of hepatic gene expression profiles between young adult C57BL/6J mice fed with a low- or a high-fat diet for 1 and 12 months.

[Thoraco-abdominal aortitis in ankylosing spondylitis: a case report and review of literature].

Unlabelled: We report a case of aortitis in a patient with ankylosing spondylitis revealed by an unexplained persistent inflammation.

Case Study: The diagnosis of ankylosing spondylitis was retained in a 64-year-old woman suffering from inflammatory back and neck pain combined with buttock pain relieved by anti-inflammatory drugs (NSAIDs) since 2004 and more recent bilateral heel pain in the morning since 2006; sacroiliitis was grade 3 on the right and grade 2 on the left (modified New-York criteria). The patient had remained asymptomatic from April 2006 to 2007 with NSAID as needed.

Coordinate Transcriptomic and Metabolomic Effects of the Insulin Sensitizer Rosiglitazone on Fundamental Metabolic Pathways in Liver, Soleus Muscle, and Adipose Tissue in Diabetic db/db Mice.

Rosiglitazone (RSG), developed for the treatment of type 2 diabetes mellitus, is known to have potent effects on carbohydrate and lipid metabolism leading to the improvement of insulin sensitivity in target tissues. To further assess the capacity of RSG to normalize gene expression in insulin-sensitive tissues, we compared groups of 18-day-treated db/db mice with increasing oral doses of RSG (10, 30, and 100 mg/kg/d) with untreated non-diabetic littermates (db/+). For this aim, transcriptional changes were measured in liver, inguinal adipose tissue (IAT) and soleus muscle using microarrays and real-time PCR.

Intimal hyperplasia in rats after subcutaneous injection of a somatostatin analog.

The somatostatin analog octreotide was administered to male and female Sprague-Dawley rats by subcutaneous injection for thirteen weeks at 0 (saline control), 0 (placebo control [mannitol and lactic acid; pH 4.2]), 1.25 mg/kg/day and 2.

S32826, a nanomolar inhibitor of autotaxin: discovery, synthesis and applications as a pharmacological tool.

Autotaxin catalyzes the transformation of lyso-phosphatidylcholine in lyso-phosphatidic acid (LPA). LPA is a phospholipid possessing a large panel of activity, in particular as a motility factor or as a growth signal, through its G-protein coupled seven transmembrane receptors. Indirect evidence strongly suggests that autotaxin is the main, if not the only source of circulating LPA.

Anticancer activity of BIM-46174, a new inhibitor of the heterotrimeric Galpha/Gbetagamma protein complex.

A large number of hormones and local agonists activating guanine-binding protein-coupled receptors (GPCR) play a major role in cancer progression. Here, we characterize the new imidazo-pyrazine derivative BIM-46174, which acts as a selective inhibitor of heterotrimeric G-protein complex. BIM-46174 prevents the heterotrimeric G-protein signaling linked to several GPCRs mediating (a) cyclic AMP generation (Galphas), (b) calcium release (Galphaq), and (c) cancer cell invasion by Wnt-2 frizzled receptors and high-affinity neurotensin receptors (Galphao/i and Galphaq).

Novel 1,3-dicarbonyl compounds having 2(3H)-benzazolonic heterocycles as PPARgamma agonists.

A series of 1,3-dicarbonyl compounds having 2(3H)-benzazolonic heterocycles has been synthesized and tested for PPARgamma agonist activity. SAR were developed and revealed that 6-acyl-2(3H)-benzothiazolone derivatives with 1,3-dicarbonyl group were the most potent. IP administration of compound 22 exhibited comparable levels of glucose and triglyceride correction to PO administration of rosiglitazone in the ob/ob mouse studies.

PIXImus DXA with different software needs individual calibration to accurately predict fat mass.

Objective: To validate GE PIXImus2 DXA fat mass (FM) estimates by chemical analysis, to compare previously published correction equations with an equation from our machine, and to determine intermachine variation.

Research Methods And Procedures: C57BL/6J (n = 16) and Aston (n = 14) mice (including ob/ob), Siberian hamsters (Phodopus sungorus) (n = 15), and bank voles (Clethrionomys glareolus) (n = 37) were DXA scanned postmortem, dried, then fat extracted using a Soxhlet apparatus. We compared extracted FM with DXA-predicted FM corrected using an equation designed using wild-type animals from split-sample validation and multiple regression and two previously published equations.

Acetylcholine-induced endothelium-dependent contractions in the SHR aorta: the Janus face of prostacyclin.

In the spontaneously hypertensive rat (SHR) and aging Wistar-Kyoto rats (WKY), acetylcholine releases an endothelium-derived contracting factor (EDCF) produced by endothelial cyclooxygenase-1, which stimulates thromboxane A2 receptors (TP receptors) on vascular smooth muscle. The purpose of the present study was to identify this EDCF by measuring changes in isometric tension and the release of various prostaglandins by acetylcholine. In isolated aortic rings of SHR, U 46619, prostaglandin (PG) H2, PGF2alpha, PGE2, PGD2, prostacyclin (PGI2) and 8-isoprostane, all activate TP receptors of the vascular smooth muscle to produce a contraction (U 46619>>8-isoprostane=PGF2alpha=PGH2>PGE2=PGD2>PGI2).

Endothelin-1 inhibits TNF alpha-induced iNOS expression in 3T3-F442A adipocytes.

1. Endothelin-1 (ET-1) and tumor necrosis factor alpha (TNFalpha) by their action on adipocytes have been independently linked to the pathogenesis of insulino-resistance. In isolated adipocytes, TNFalpha induces the expression of the inducible nitric oxide synthase (iNOS).

High level of uncoupling protein 1 expression in muscle of transgenic mice selectively affects muscles at rest and decreases their IIb fiber content.

The mitochondrial uncoupling protein of brown adipose tissue (UCP1) was expressed in skeletal muscle and heart of transgenic mice at levels comparable with the amount found in brown adipose tissue mitochondria. These transgenic mice have a lower body weight, and when related to body weight, food intake and energy expenditure are increased. A specific reduction of muscle mass was observed but varied according to the contractile activity of muscles.

Regulation of murine airway responsiveness by endothelial nitric oxide synthase.

Nitric oxide (NO) is a potent vasodilator, but it can also modulate contractile responses of the airway smooth muscle. Whether or not endothelial (e) NO synthase (NOS) contributes to the regulation of bronchial tone is unknown at present. Experiments were designed to investigate the isoforms of NOS that are expressed in murine airways and to determine whether or not the endogenous release of NO modulates bronchial tone in wild-type mice and in mice with targeted deletion of eNOS [eNOS(-/-)].

Inhibition of human tumor cell growth in vivo by an orally bioavailable inhibitor of human farnesyltransferase, BIM-46228.

Oncogenic mutations of the ras gene leading to constitutive activation of downstream effectors have been detected in a wide spectrum of human cancers (pancreas, thyroid, colon, non-small-cell lung cancer). Membrane anchorage of Ras, required for functional activity in signal transduction, is facilitated by post-translational modifications resulting in covalent attachment of a farnesyl group to the cysteine in the C-terminal CAAX motif. This attachment is mediated by farnesyltransferase (FTase).

Hyperoxia/normoxia-driven retinal angiogenesis in mice: a role for angiotensin II.

Purpose: To examine a possible role for the angiotensin system in a rodent model of retinopathy of prematurity.

Methods: A previously described model was used in which oxygen cycling (5 days hyperoxia and 5 days hypoxia) induced retinal alterations in newborn mice. An angiotensin-converting enzyme inhibitor (perindopril), or angiotensin receptor antagonists AT1 (losartan) or AT2 (PD123319) were administered subcutaneously for 5 days after the hyperoxia exposure.

Inhibition of human tumor cell growth in vitro and in vivo by a specific inhibitor of human farnesyltransferase: BIM-46068.

Oncogenic mutations of the ras gene leading to constitutive activation of downstream effectors have been detected in a large spectrum of human cancers (pancreas, thyroid, colon and NSCLC). Membrane anchorage of Ras required for functional activity in signal transduction is facilitated by post-translational modifications resulting in covalent attachment of a farnesyl group to the cysteine in the C-terminal CAAX motif. This attachment is mediated by farnesyltransferase (FTase).

Sequence dependency of the internalization and distribution of phosphorothioate oligonucleotides in vascular smooth muscle cells.

Antisense studies imply the utilization of oligonucleotides (ODN) for sequence-specific down-regulation of genes. This usually consists in assessing antisense sequences versus control sequences (mismatched, inverted, scrambled, randomized or any sequence unrelated to the relevant target). Even though the investigated biological effect (knockdown of an unwanted protein) is observed only with the antisense sequence and weakly, if at all, with any of the control sequences, this is a necessary but not a sufficient condition to demonstrate an antisense effect.

Dual inhibition of human leukocyte elastase and lipid peroxidation: in vitro and in vivo activities of azabicyclo[2.2.2]octane and perhydroindole derivatives.

A series of potent and selective human leukocyte elastase (HLE) inhibitors of the Val-Pro-Val type has been developed. Initially, the central proline residue was replaced by nonnatural amino acids Phi ((2S,3aS,7aS)-perhydroindole-2-carboxylic acid) and Abo ((3S)-2-azabicyclo-[2.2.

Neutrophil-associated inflammatory responses in rats are inhibited by phenylarsine oxide.

NADPH oxidase is a phagocyte-specific enzyme which produces O2- and so initiates a cascade of reactive oxygen species formation. Inflammatory diseases involve overproduction of reactive oxygen species which induce tissue damage. Phenylarsine oxide has been described previously as a complete and direct inhibitor of NADPH oxidase in vitro that acts by covalently binding to vicinal thiol groups of a membrane-associated component of the enzyme.

Activation of MMP-9 by neutrophil elastase in an in vivo model of acute lung injury.

The effect of neutrophil elastase on the functional status of gelatinases was studied in an hamster model developed by intratracheal administration of lipopolysaccharide followed by in situ cell activation with phorbol myristate acetate. This resulted in the production in bronchoalveolar lavage fluids, in addition to the matrix metalloproteinase MMP-9, of a 75 kDa gelatinase associated with collagenolytic activity. Treatment in vivo with an elastase inhibitor abolished the latter activity.

In vitro down-regulation of antigen-induced IL-5 gene expression and protein production by cAMP-specific phosphodiesterase type 4 inhibitor.

The effects of cAMP-elevating agents on antigen-induced IL-5 (interleukin-5) messenger RNA expression and protein production were examined in vitro in an antigen-driven system of splenocytes from ovalbumin sensitized BALB/c mice. IL-5 production was inhibited by rolipram, a type 4 phosphodiesterase (PDE4) inhibitor, dose-dependently (maximally at 10(-5) M) and by dibutyryl-cAMP (db-cAMP) (3 x 10(-4) M), but not by the type 3 and type 5 PDE inhibitors milrinone and zaprinast (10(-5) M), respectively. Forskolin (10(-5) M), an adenylate cyclase activator, was noninhibitory alone but potentiated inhibition by rolipram.

A water-soluble, stable dipeptide NK1 receptor-selective neurokinin receptor antagonist with potent in vivo pharmacological effects: S18523.

The potassium salt of a chemically stabilized dipeptide, {1-[4-(1 H-tetrazol-5-yl)butyl]indol-3-yl}carbonyl-Hyp-Nal-N(methyl)-Bzl , (Hyp = (R)-4-hydroxy-L-proline; Nal = 3-L-(beta-naphthyl)-alanine), S18523, is described as a new water-soluble, potent and selective NK1 receptor antagonist. The low molecular weight antagonist (M(r) = 736) displays nanomolar potency (pA2 = 9.6) in the rabbit vena cava (NK1) bioassay and nanomolar affinity (pKi = 9.

In vitro pharmacological effects of S 12370 (2-[4-benzhydryloxypiperidinoethyl]isoxindole; an antibronchoconstrictor agent) in normal and sensitized tissue.

The effects of S 12370 (2-[4-benzhydryloxypiperidinoethyl]isoxindole), were studied in vitro. In guinea pig isolated tracheal rings, S 12370 induced a similar competitive inhibition of the contractile responses produced by acetylcholine, histamine and serotonin. However, it did not affect the contractions induced by leukotriene D4 (LTD4), substance P and U 46619, a stable analogue of thromboxane A2.