Role of breast regression protein-39/YKL-40 in asthma and allergic responses

BRP-39 and its human homolog YKL-40 have been regarded as a prototype of chitinase-like proteins (CLP) in mammals. Exaggerated levels of YKL-40 protein and/or mRNA have been noted in a number of diseases characterized by inflammation, tissue remodeling, and aberrant cell growth. Asthma is an inflammatory disease characterized by airway hyperresponsiveness and airway remodeling. Recently, the novel regulatory role of BRP-39/YKL-40 in the pathogenesis of asthma has been demonstrated both in human studies and allergic animal models. The levels of YKL-40 are increased in the circulation and lungs from asthmatics where they correlate with disease severity, and CHI3L1 polymorphisms correlate with serum YKL-40 levels, asthma and abnormal lung function. Animal studies using BRP-39 null mutant mice demonstrated that BRP-39 was required for optimal allergen sensitization and Th2 inflammation. These studies suggest the potential use of BRP-39 as a biomarker as well as a therapeutic target for asthma and other allergic diseases. Here, we present an overview of chitin/chitinase biology and summarize recent findings on the role of BRP-39 in the pathogenesis of asthma and allergic responses

Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13–induced tissue responses and apoptosis

Mouse breast regression protein 39 (BRP-39; Chi3l1) and its human homologue YKL-40 are chitinase-like proteins that lack chitinase activity. Although YKL-40 is expressed in exaggerated quantities and correlates with disease activity in asthma and many other disorders, the biological properties of BRP-39/YKL-40 have only been rudimentarily defined. We describe the generation and characterization of BRP-39−/− mice, YKL-40 transgenic mice, and mice that lack BRP-39 and produce YKL-40 only in their pulmonary epithelium. Studies of these mice demonstrated that BRP-39−/− animals have markedly diminished antigen-induced Th2 responses and that epithelial YKL-40 rescues the Th2 responses in these animals. The ability of interleukin13 to induce tissue inflammation and fibrosis was also markedly diminished in the absence of BRP-39. Mechanistic investigations demonstrated that BRP-39 and YKL-40 play an essential role in antigen sensitization and immunoglobulin E induction, stimulate dendritic cell accumulation and activation, and induce alternative macrophage activation. These proteins also inhibit inflammatory cell apoptosis/cell death while inhibiting Fas expression, activating protein kinase B/AKT, and inducing Faim 3. These studies establish novel regulatory roles for BRP-39/YKL-40 in the initiation and effector phases of Th2 inflammation and remodeling and suggest that these proteins are therapeutic targets in Th2- and macrophage-mediated disorders

Selenium in reproduction

Selenium is an essential trace element of importance to human biology and health. Increasing evidence suggests that this mineral plays an important role in normal growth and reproduction in animals and humans, and selenium supplementation is now recommended as part of public health policy in geographical areas with severe selenium deficiency in soil. This review addresses the biological functions of selenium followed by a detailed review of associations between selenium status and reproductive health. In many countries, selenium dietary intake falls below the recommended nutrient intakes and is inadequate to support maximal expression of the selenoenzymes. Numerous reports implicate selenium deficiency in several reproductive and obstetric complications including male and female infertility, miscarriage, preeclampsia, fetal growth restriction, preterm labor, gestational diabetes, and obstetric cholestasis. Currently, there is inadequate information from the available small intervention studies to inform public health strategies. Larger intervention trials are required to reinforce or refute a beneficial role of selenium supplementation in disorders of reproductive health

Wide-field and two-photon imaging of brain activity with voltage- and calcium-sensitive dyes.: Imaging brain activity

International audienceThis chapter presents three examples of imaging brain activity with voltage- or calcium-sensitive dyes. Because experimental measurements are limited by low sensitivity, the chapter then discusses the methodological aspects that are critical for optimal signal-to-noise ratio. Two of the examples use wide-field (1-photon) imaging and the third uses two-photon scanning microscopy. These methods have relatively high temporal resolution ranging from 10 to 10,000 Hz. The three examples are the following: (1) Internally injected voltage-sensitive dye can be used to monitor membrane potential in the dendrites of invertebrate and vertebrate neurons in in vitro preparations. These experiments are directed at understanding how individual neurons convert the complex input synaptic activity into the output spike train. (2) Recently developed methods for staining many individual cells in the mammalian brain with calcium-sensitive dyes together with two-photon microscopy made it possible to follow the spike activity of many neurons simultaneously while in vivo preparations are responding to stimulation. (3) Calcium-sensitive dyes that are internalized into olfactory receptor neurons in the nose will, after several days, be transported to the nerve terminals of these cells in the olfactory bulb glomeruli. There, the population signals can be used as a measure of the input from the nose to the bulb. Three kinds of noise in measuring light intensity are discussed: (1) Shot noise from the random emission of photons from the preparation. (2) Extraneous (technical) noise from external sources. (3) Noise that occurs in the absence of light, the dark noise. In addition, we briefly discuss the light sources, the optics, and the detectors and cameras. The commonly used organic voltage and ion sensitive dyes stain all of the cell types in the preparation indiscriminately. A major effort is underway to find methods for staining individual cell types in the brain selectively. Most of these efforts center around fluorescent protein activity sensors because transgenic methods can be used to express them in individual cell types

Endolysins as Antimicrobials

Bacteriophages, Part BPeptidoglycan (PG) is the major structural component of the bacterial cell wall. Bacteria have autolytic PG hydrolases that allow the cell to grow and divide. A well-studied group of PG hydrolase enzymes are the bacteriophage endolysins. Endolysins are PG-degrading proteins that allow the phage to escape from the bacterial cell during the phage lytic cycle. The endolysins, when purified and exposed to PG externally, can cause > lysis from without.> Numerous publications have described how this phenomenon can be used therapeutically as an effective antimicrobial against certain pathogens. Endolysins have a characteristic modular structure, often with multiple lytic and/or cell wall-binding domains (CBDs). They degrade the PG with glycosidase, amidase, endopeptidase, or lytic transglycosylase activities and have been shown to be synergistic with fellow PG hydrolases or a range of other antimicrobials. Due to the coevolution of phage and host, it is thought they are much less likely to invoke resistance. Endolysin engineering has opened a range of new applications for these proteins from food safety to environmental decontamination to more effective antimicrobials that are believed refractory to resistance development. To put phage endolysin work in a broader context, this chapter includes relevant studies of other well-characterized PG hydrolase antimicrobials. © 2012 Elsevier Inc.This work was supported in part by NIH Grant 1RO1AI075077-01A1; NRI Grant 2007-35204-18395, and U.S. state department funds, all awards to DMD.Peer Reviewe

Involvement of CYP1B1 in interferon γ-induced alterations of epithelial barrier integrity.

BACKGROUND AND PURPOSE: CYP1B1 and CYP1A1 are important extra-hepatic cytochromes, expressed in the colon and involved in the metabolism of dietary constituents and exogenous compounds. CYP1B1 expression is increased by pro-inflammatory cytokines, and it has been recently implicated in regulation of blood brain barrier function. We investigated its involvement in the increased permeability of the intestinal epithelial barrier observed in inflammatory conditions. EXPERIMENTAL APPROACH: Epithelial monolayers formed by human T84 colon carcinoma cells cultured on transwells, were disrupted by incubation with IFNγ (10 ng·mL-1 ). Monolayer integrity was measured using transepithelial electrical resistance. CYP1A1 and CYP1B1 inhibitors or inducers were applied apically. Potential mechanisms of action were investigated using RT-qPCR. KEY RESULTS: IFNγ disrupts the barrier integrity of the T84 monolayers and increases CYP1B1 and HIF1α mRNA expression. CYP1B1 induction is inhibited by the NF-κB inhibitor ammonium pyrrolidinedithiocarbamate (100 μM) but not by the HIF1α inhibitor 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (50 μM). Inhibition of CYP1B1 with the selective inhibitor 2,4,3',5'-tetramethoxystilbene (100 nM) partly reverses the effects of IFNγ on epithelial permeability. CONCLUSIONS AND IMPLICATIONS: These data suggest that increased expression of CYP1B1 is involved in the effects of IFNγ on epithelial permeability. Inhibition of CYP1B1 counteracts the alterations of epithelial barrier integrity induced by IFNγ and could thus have a therapeutic potential in disorders of intestinal permeability associated with inflammation