Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts.

The bone marrow niche is thought to act as a permissive microenvironment required for emergence or progression of hematologic cancers. We hypothesized that osteoblasts, components of the niche involved in hematopoietic stem cell (HSC) function, influence the fate of leukemic blasts. We show that osteoblast numbers decrease by 55% in myelodysplasia and acute myeloid leukemia patients.

Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts.

Cells of the osteoblast lineage affect the homing and the number of long-term repopulating haematopoietic stem cells, haematopoietic stem cell mobilization and lineage determination and B cell lymphopoiesis. Osteoblasts were recently implicated in pre-leukaemic conditions in mice. However, a single genetic change in osteoblasts that can induce leukaemogenesis has not been shown.

FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin.

Serotonin is a critical regulator of bone mass, fulfilling different functions depending on its site of synthesis. Brain-derived serotonin promotes osteoblast proliferation, whereas duodenal-derived serotonin suppresses it. To understand the molecular mechanisms of duodenal-derived serotonin action on osteoblasts, we explored its transcriptional mediation in mice.

FoxO1 protein cooperates with ATF4 protein in osteoblasts to control glucose homeostasis.

The Forkhead transcription factor FoxO1 inhibits through its expression in osteoblasts β-cell proliferation, insulin secretion, and sensitivity. At least part of the FoxO1 metabolic functions result from its ability to suppress the activity of osteocalcin, an osteoblast-derived hormone favoring glucose metabolism and energy expenditure. In searching for mechanisms mediating the metabolic actions of FoxO1, we focused on ATF4, because this transcription factor also affects glucose metabolism through its expression in osteoblasts.

Genetic evidence points to an osteocalcin-independent influence of osteoblasts on energy metabolism.

The skeleton has been shown recently to regulate glucose metabolism through an osteoblast-specific hormone, osteocalcin, which favors β-cell proliferation, insulin secretion, insulin sensitivity, and energy expenditure. An implication of this finding is that a decrease in osteoblast numbers would compromise glucose metabolism in an osteocalcin-dependent manner. To test this hypothesis, osteoblasts were inducibly ablated by cross-breeding transgenic mice expressing a tamoxifen-regulated Cre under the control of the osteocalcin promoter with mice in which an inactive form of the diphtheria toxin A chain was introduced into a ubiquitously expressed locus.

Genetic determination of the cellular basis of the sympathetic regulation of bone mass accrual.

The sympathetic nervous system, whose activity is regulated by leptin signaling in the brain, is a major regulator of bone mass accrual. To determine the identity of the cell type in which the sympathetic tone signals to inhibit bone mass accrual, we performed a systematic, cell-specific analysis of the function of the β2 adrenergic receptor (Adrβ2) and various genes implicated in the pathway in the mouse. This was followed by leptin intracerebroventricular (ICV) infusion and bone histomorphometric analyses of bone parameters.

FoxO1 is a positive regulator of bone formation by favoring protein synthesis and resistance to oxidative stress in osteoblasts.

Osteoporosis, a disease of low bone mass, is associated with decreased osteoblast numbers and increased levels of oxidative stress within osteoblasts. Since transcription factors of the FoxO family confer stress resistance, we investigated their potential impact on skeletal integrity. Here we employ cell-specific deletion and molecular analyses to show that, among the three FoxO proteins, only FoxO1 is required for proliferation and redox balance in osteoblasts and thereby controls bone formation.

FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice.

Osteoblasts have recently been found to play a role in regulating glucose metabolism through secretion of osteocalcin. It is unknown, however, how this osteoblast function is regulated transcriptionally. As FoxO1 is a forkhead family transcription factor known to regulate several key aspects of glucose homeostasis, we investigated whether its expression in osteoblasts may contribute to its metabolic functions.

Genetic ablation of NADPH oxidase enhances susceptibility to cigarette smoke-induced lung inflammation and emphysema in mice.

Cigarette smoke (CS) induces recruitment of inflammatory cells in the lungs leading to the generation of reactive oxygen species (ROS), which are involved in lung inflammation and injury. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a multimeric system that is responsible for ROS production in mammalian cells. We hypothesized that NADPH oxidase-derived ROS play an important role in lung inflammation and injury and that targeted ablation of components of NADPH oxidase (p47(phox) and gp91(phox)) would protect lungs against the detrimental effects of CS.

IKK alpha causes chromatin modification on pro-inflammatory genes by cigarette smoke in mouse lung.

Cigarette smoke (CS) induces abnormal and sustained lung inflammation; however, the molecular mechanism underlying sustained inflammation is not known. It is well known that activation of I kappaB kinase beta (IKK beta) leads to transient translocation of active NF-kappaB (RelA/p65-p50) in the nucleus and transcription of pro-inflammatory genes, whereas the role of IKK alpha in perpetuation of sustained inflammatory response is not known. We hypothesized that CS activates IKK alpha and causes histone acetylation on the promoters of pro-inflammatory genes, leading to sustained transcription of pro-inflammatory mediators in mouse lung in vivo and in human monocyte/macrophage cell line (MonoMac6) in vitro.

Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells.

Nuclear erythroid-related factor 2 (Nrf2), a redox-sensitive transcription factor, is involved in transcriptional regulation of many antioxidant genes, including glutamate-cysteine ligase (GCL). Cigarette smoke (CS) is known to cause oxidative stress and deplete glutathione (GSH) levels in alveolar epithelial cells. We hypothesized that resveratrol, a polyphenolic phytoalexin, has antioxidant signaling properties by inducing GSH biosynthesis via the activation of Nrf2 and protects lung epithelial cells against CS-mediated oxidative stress.

Rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, PPARgamma agonists, differentially regulate cigarette smoke-mediated pro-inflammatory cytokine release in monocytes/macrophages.

Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) ligands have the potential for use as anti-inflammatory agents in chronic airway diseases. We hypothesized that cigarette smoke (CS)-mediated pro-inflammatory cytokine release would be downregulated in the monocyte-macrophage cell line (MonoMac6) by synthetic and natural PPARgamma ligands. Surprisingly, treatment of MonoMac6 cells with the natural PPARgamma ligand 15-deoxy-Delta12,14-prostaglandin J2 led to increased cytokine (IL-8) release in response to either TNF-alpha or CS extract (CSE).

Azithromycin suppresses activation of nuclear factor-kappa B and synthesis of pro-inflammatory cytokines in tracheal aspirate cells from premature infants.

Nuclear factor-kappaB (NF-kappaB) plays a central role in regulating key proinflammatory mediators. The activation of NF-kappaB is increased in tracheal aspirate (TA) cells from premature infants developing bronchopulmonary dysplasia (BPD). We studied the effect of azithromycin (AZM) on the suppression of NF-kappaB activation and the synthesis of pro-inflammatory cytokines IL-6 and IL-8 by TA cells obtained from premature infants.

Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method.

The spectrophotometric/microplate reader assay method for glutathione (GSH) involves oxidation of GSH by the sulfhydryl reagent 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB) to form the yellow derivative 5'-thio-2-nitrobenzoic acid (TNB), measurable at 412 nm. The glutathione disulfide (GSSG) formed can be recycled to GSH by glutathione reductase in the presence of NADPH. The assay is composed of two parts: the preparation of cell cytosolic/tissue extracts and the detection of total glutathione (GSH and GSSG).

Role of an aminothiazole derivative on ethanol-induced toxicity.

ABSTRACT The protective effect of dendrodoine analog (DA) [4-amino-5-benzoyl-2-(4-methoxy phenylamino) thiazole] at three doses (5, 10, and 15 mg/kg body weight) was investigated on ethanol-induced hyperlipidemia. Hepatotoxicity was induced by administering 7.9 g ethanol/kg body weight for 45 days by intragastric intubation.

Differential effects of cigarette smoke on oxidative stress and proinflammatory cytokine release in primary human airway epithelial cells and in a variety of transformed alveolar epithelial cells.

Background: Cigarette smoke mediated oxidative stress and inflammatory events in the airway and alveolar epithelium are important processes in the pathogenesis of smoking related pulmonary diseases. Previously, individual cell lines were used to assess the oxidative and proinflammatory effects of cigarette smoke with confounding results. In this study, a panel of human and rodent transformed epithelial cell lines were used to determine the effects of cigarette smoke extract (CSE) on oxidative stress markers, cell toxicity and proinflammatory cytokine release and compared the effects with that of primary human small airway epithelial cells (SAEC).

Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-kappaB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging.

The silent information regulator 2 (Sir2) family of proteins (sirtuins or SIRTs), which belong to class III histone/protein deacetylases, have been implicated in calorie restriction, aging, and inflammation. We hypothesized that cigarette smoke-mediated proinflammatory cytokine release is regulated by SIRT1 by its interaction with NF-kappaB in a monocyte-macrophage cell line (MonoMac6) and in inflammatory cells of rat lungs. Cigarette smoke extract (CSE) exposure to MonoMac6 cells caused dose- and time-dependent decreases in SIRT1 activity and levels, which was concomitant to increased NF-kappaB-dependent proinflammatory mediator release.

A surprising twist: an unusual failure of a keyed filling device specific for a volatile inhaled anesthetic.

We describe two cases in which keyed filling devices for sevoflurane were inadvertently screwed onto isoflurane bottles. The mishaps were possible because the collars on sevoflurane and isoflurane bottles are mirror images of each other. The particular keyed filling device was designed with a flexible outer sleeve and could be screwed onto the wrong bottle while slightly gouging its soft plastic collar.

Oxidant and antioxidant balance in the airways and airway diseases.

Although oxygen is a prerequisite to life, at concentrations beyond the physiological limits it may be hazardous to the cells. Since the lungs are directly exposed to very high amounts of oxygen, it is imperative for the organ to possess defences against possible oxidative challenge. The lungs are therefore endowed with an armamentarium of a battery of endogenous agents called antioxidants.

Differential induction of apoptosis by cigarette smoke extract in primary human lung fibroblast strains: implications for emphysema.

Cigarette smoke is the principal cause of emphysema. Recent attention has focused on the loss of alveolar fibroblasts in the development of emphysema. Fibroblasts may become damaged by oxidative stress and undergo apoptosis as a result of cigarette smoke exposure.

Changes in Activities of MMP in Alcohol and Thermally Oxidized Sunflower Oil-Induced Liver Damage: NAC Antioxidant Therapy.

Liver fibrosis is the result of imbalance between extracellular matrix (ECM) synthesis and breakdown. Ethanol-induced increase in redox state is a sign of major change in hepatic metabolism and this inhibits tricarboxylic acid cycle activity and, fatty acid oxidation and increases fatty acid uptake, thus predisposing fatty liver. Fibrotic changes induced by alcohol are provoked by diets rich in PUFA.

Comparative effects of curcumin and its analog on alcohol- and polyunsaturated fatty acid-induced alterations in circulatory lipid profiles.

Excessive alcohol intake induces hyperlipidemia. Studies suggest that natural principles and their analogs are known to possess anti-hyperlipidemic properties. In the present work we tested the effect of curcumin, an active principle of turmeric (Curcuma longa), and a curcumin analog on alcohol- and thermally oxidized polyunsaturated fatty acid (deltaPUFA)- induced hyperlipidemia.

Expression pattern of matrix metalloproteinases in alcohol- and thermally oxidized sunflower oil-induced toxicity: protective role of an aminothiazole derivative.

The matrix metalloproteinases (MMPs) are a family of secreted and membrane-bound zinc endopeptidases. Collectively, these enzymes can degrade all of the components of the extracellular matrix including collagen, fibronectin, laminin, and basement membrane glycoproteins. Regulation in expression and activation of proteinases is one of the most important mechanisms in organ morphogenesis.

Effect of ethanol and thermally oxidized sunflower oil ingestion on phospholipid fatty acid composition of rat liver: protective role of Cuminum cyminum L.

Aim: The current study was undertaken to assess the effect of ethanol and thermally oxidized sunflower oil ingestion on liver phospholipid fatty acids and the protective role of Cuminum cyminum L.

Methods: Ethanol was administered at a level of 20% and thermally oxidized sunflower oil at a level of 15% for 45 days. C.