Quercetin prevents progression of disease in elastase/LPS-exposed mice by negatively regulating MMP expression

Abstract Background Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, emphysema and irreversible airflow limitation. These changes are thought to be due to oxidative stress and an imbalance of proteases and antiproteases. Quercetin, a plant flavonoid, is a potent antioxidant and anti-inflammatory agent. We hypothesized that quercetin reduces lung inflammation and improves lung function in elastase/lipopolysaccharide (LPS)-exposed mice which show typical features of COPD, including airways inflammation, goblet cell metaplasia, and emphysema. Methods Mice treated with elastase and LPS once a week for 4 weeks were subsequently administered 0.5 mg of quercetin dihydrate or 50% propylene glycol (vehicle) by gavage for 10 days. Lungs were examined for elastance, oxidative stress, inflammation, and matrix metalloproteinase (MMP) activity. Effects of quercetin on MMP transcription and activity were examined in LPS-exposed murine macrophages. Results Quercetin-treated, elastase/LPS-exposed mice showed improved elastic recoil and decreased alveolar chord length compared to vehicle-treated controls. Quercetin-treated mice showed decreased levels of thiobarbituric acid reactive substances, a measure of lipid peroxidation caused by oxidative stress. Quercetin also reduced lung inflammation, goblet cell metaplasia, and mRNA expression of pro-inflammatory cytokines and muc5AC. Quercetin treatment decreased the expression and activity of MMP9 and MMP12 in vivo and in vitro, while increasing expression of the histone deacetylase Sirt-1 and suppressing MMP promoter H4 acetylation. Finally, co-treatment with the Sirt-1 inhibitor sirtinol blocked the effects of quercetin on the lung phenotype. Conclusions Quercetin prevents progression of emphysema in elastase/LPS-treated mice by reducing oxidative stress, lung inflammation and expression of MMP9 and MMP12.http://deepblue.lib.umich.edu/bitstream/2027.42/78260/1/1465-9921-11-131.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78260/2/1465-9921-11-131.pdfPeer Reviewe

Mechanistic Insight into the Enzymatic Reduction of Truncated Hemoglobin N of Mycobacterium tuberculosis: role of the CD loop and pre-A Motif in electron cycling

Background: The HbN of Mycobacterium tuberculosis carries a potent nitric-oxide dioxygenase activity despite lacking a reductase domain. Results: The NADH-ferredoxin reductase system acts as an efficient partner for the reduction of HbN. Conclusion: The interactions of HbN with the reductase are modulated by its CD loop and the Pre-A region. Significance: The present study provides new insights into the mechanism of electron transfer during nitric oxide detoxification by HbN.Fil: Singh, Sandeep. Institute of Microbial Technology; IndiaFil: Thakur, Naveen. Institute of Microbial Technology; IndiaFil: Oliveira, Ana. Universidad de Barcelona; EspañaFil: Petruk, Ariel Alcides. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Hade, Mangesh Dattu. Institute of Microbial Technology; IndiaFil: Sethi, Deepti. Institute of Microbial Technology; IndiaFil: Bidon Chanal, Axel. Universidad de Barcelona; EspañaFil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Datta, H.. Institute of Microbial Technology; IndiaFil: Parkesh, R.. Institute of Microbial Technology; IndiaFil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Luque, F. Javier. Universidad de Barcelona; EspañaFil: Dikshit, Kanak L.. Institute of Microbial Technology; Indi

Isolation and characterization of Alicycliphilus denitrificans strain BC, which grows on benzene with chlorate as the electron acceptor

A bacterium, strain BC, was isolated from a benzene-degrading chlorate-reducing enrichment culture. Strain BC degrades benzene in conjunction with chlorate reduction. Cells of strain BC are short rods that are 0.6 microm wide and 1 to 2 microm long, are motile, and stain gram negative. Strain BC grows on benzene and some other aromatic compounds with oxygen or in the absence of oxygen with chlorate as the electron acceptor. Strain BC is a denitrifying bacterium, but it is not able to grow on benzene with nitrate. The closest cultured relative is Alicycliphilus denitrificans type strain K601, a cyclohexanol-degrading nitrate-reducing betaproteobacterium. Chlorate reductase (0.4 U/mg protein) and chlorite dismutase (5.7 U/mg protein) activities in cell extracts of strain BC were determined. Gene sequences encoding a known chlorite dismutase (cld) were not detected in strain BC by using the PCR primers described in previous studies. As physiological and biochemical data indicated that there was oxygenation of benzene during growth with chlorate, a strategy was developed to detect genes encoding monooxygenase and dioxygenase enzymes potentially involved in benzene degradation in strain BC. Using primer sets designed to amplify members of distinct evolutionary branches in the catabolic families involved in benzene biodegradation, two oxygenase genes putatively encoding the enzymes performing the initial successive monooxygenations (BC-BMOa) and the cleavage of catechol (BC-C23O) were detected. Our findings suggest that oxygen formed by dismutation of chlorite can be used to attack organic molecules by means of oxygenases, as exemplified with benzene. Thus, aerobic pathways can be employed under conditions in which no external oxygen is supplie

Remodeling Of The Bone Tissue Of Rats Of Different Lines After Melatonin Effect

The markers of remodeling of bone tissue (BT) were studied after the impact of pharmacologic dose of melatonin (5 mg/kg of the animal body weight) during 28 days for 3-months rats-males of Wistar and SHR lines. The studies were carried out in autumn. The aim of our work was to study the indices of bone tissue remodeling of rats of Wistar and SHR lines after introduction of pharmacologic dose of exogenous melatonin.Biochemical and immune-enzyme methods of analysis were used in the study. In rats of Wistar line was revealed a reliable increase of activity of alkaline phosphatase (ALP) by 43,9% (Р<0,05), hyaluronidase activity (HA) by 15,4% and free thyroxin concentration (fТ4) by 30%. There was also registered the decrease of pyridinoline (PYD) concentration by 48% and glycosaminoglycan (GAG) by 46,7%. In rats of SHR line under the same conditions the results essentially differed. The activity of acid phosphatase (ACP) has a tendency to increase by 11,6%, and PYD concentration decreased by 25%. The concentrations of free triiodothyronine (fТ3) and fТ4 reliably increased by 51,3% and 31,1% respectively.In the result of research we revealed that melatonin plays the main role among several main factors of regulation of bone tissue remodeling. It has stimulating influence on bone tissue and hormones of thyroid gland

Inhibition of MAPK-Erk pathway in vivo attenuates aortic valve disease processes in Emilin1-deficient mouse model

Aortic valve disease (AVD) is a common condition with a progressive natural history, and presently, there are no pharmacologic treatment strategies. Elastic fiber fragmentation (EFF) is a hallmark of AVD, and increasing evidence implicates developmental elastic fiber assembly defects. Emilin1 is a glycoprotein necessary for elastic fiber assembly that is present in both developing and mature human and mouse aortic valves. The Emilin1‐deficient mouse (Emilin1 (−/−)) is a model of latent AVD, characterized by activated TGFβ/MEK/p‐Erk signaling and upregulated elastase activity. Emilin1 (−/−) aortic valves demonstrate early EFF and aberrant angiogenesis followed by late neovascularization and fibrosis. The objective of this study was to test the effectiveness of three different targeted therapies. Aged (12–14 months) Emilin1 (−/−) mice were treated with refametinib (RDEA‐119, MEK1/2 inhibitor), doxycycline (elastase inhibitor), or G6‐31 (anti‐VEGF‐A mouse antibody) for 4 weeks. Refametinib‐ and doxycycline‐treated Emilin1 (−/−) mice markedly reduced MEK/p‐Erk activation in valve tissue. Furthermore, both refametinib and doxycycline attenuated elastolytic cathepsin K, L, MMP‐2, and MMP‐9 activation, and abrogated macrophage and neutrophil infiltration in Emilin1 (−/−) aortic valves. RNAseq analysis was performed in aortic valve tissue from adult (4 months) and aged (14 months) Emilin1 (−/−) and age‐matched wild‐type control mice, and demonstrated upregulation of genes associated with MAPK/MEK/p‐Erk signaling and elastases at the adult stage and inflammatory pathways at the aged stage controlling for age. These results suggest that Erk1/2 signaling is an important modulator of early elastase activation, and pharmacological inhibition using refametinib may be a promising treatment to halt AVD progressio

Using Graph Transformations and Graph Abstractions for Software Verification

In this paper we describe our intended approach for the verification of software written in imperative programming languages. We base our approach on model checking of graph transition systems, where each state is a graph and the transitions are specified by graph transformation rules. We believe that graph transformation is a very suitable technique to model the execution semantics of languages with dynamic memory allocation. Furthermore, such representation allows us to investigate the use of graph abstractions, which can mitigate the combinatorial explosion inherent to model checking. In addition to presenting our planned approach, we reason about its feasibility, and, by providing a brief comparison to other existing methods, we highlight the benefits and drawbacks that are expected