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

The influence of 2- chlorodeoxyadenosine in combination with tumour necrosis factor-α or its mutein on murine leukaemias L1210 and P388

We investigated the influence of 2-chlorodeoxyadenosine (2-CdA) in combination with tumour necrosis factor-α (TNFα) or its mutein VI, which differs from the native molecule by N-terminal amino acid composition, on the survival time of mice inoculated with leukaemia L1210 or P388. Groups of mice with leukaemia L1210 and P388 receiving 2-CdA combined with TNFα had shorter survival times than animals treated with these agents separately. In contrast, the administration of 2-CdA in conjunction with mutein VI, prolonged the survival of mice inoculated with these leukaemias as compared with animals receiving these agents separately. The results of the present study emphasize the importance of the biological activity of the TNFα molecule N-terminus

A comparison of the Antileukaemic Effects of Recombinant Human Tumour Necrosis Factor-α and its Muteins on Leukaemia L1210 and Leukaemia P388 in Mice

We investigated the influence of recombinant human tumour necrosis factor alpha (TNF-α) and its derivatives termed muteins III, V, VI—in which the first 3 to 7 amino acids of native TNF-α have been replaced—on the survival time of mice inoculated with leukaemia L1210 or leukaemia P338. TNF-α prolonged the survival of mice with leukaemia L1210 but did not have any therapeutic activity in leukaemia P388-bearing mice. Muteins-treated mice with leukaemia P388 lived longer than animals receiving TNF-α, while those inoculated with leukaemia L1210 did not show any significant prolongation of life compared with the TNF-α treated group. The results presented in this report indicate that the antileukaemic activity of TNF-α is governed at least in part by the nature of the N-terminal amino acids

Copper-catalysed selective hydroamination reactions of alkynes

The development of selective reactions that utilize easily available and abundant precursors for the efficient synthesis of amines is a long-standing goal of chemical research. Despite the centrality of amines in a number of important research areas, including medicinal chemistry, total synthesis and materials science, a general, selective and step-efficient synthesis of amines is still needed. Here, we describe a set of mild catalytic conditions utilizing a single copper-based catalyst that enables the direct preparation of three distinct and important amine classes (enamines, α-chiral branched alkylamines and linear alkylamines) from readily available alkyne starting materials with high levels of chemo-, regio- and stereoselectivity. This methodology was applied to the asymmetric synthesis of ​rivastigmine and the formal synthesis of several other pharmaceutical agents, including ​duloxetine, ​atomoxetine, ​fluoxetine and ​tolterodine.National Institutes of Health (U.S.) (GM58160

Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience

Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various CD20-expressing lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin lymphoma. Since its first approval 20 years ago, intravenously administered rituximab has revolutionized the treatment of B-cell malignancies and has become a standard component of care for follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. For all of these diseases, clinical trials have demonstrated that rituximab not only prolongs the time to disease progression but also extends overall survival. Efficacy benefits have also been shown in patients with marginal zone lymphoma and in more aggressive diseases such as Burkitt lymphoma. Although the proven clinical efficacy and success of rituximab has led to the development of other anti-CD20 monoclonal antibodies in recent years (e.g., obinutuzumab, ofatumumab, veltuzumab, and ocrelizumab), rituximab is likely to maintain a position within the therapeutic armamentarium because it is well established with a long history of successful clinical use. Furthermore, a subcutaneous formulation of the drug has been approved both in the EU and in the USA for the treatment of B-cell malignancies. Using the wealth of data published on rituximab during the last two decades, we review the preclinical development of rituximab and the clinical experience gained in the treatment of hematologic B-cell malignancies, with a focus on the well-established intravenous route of administration. This article is a companion paper to A. Davies, et al., which is also published in this issue

The neuronal structure of the dorsal nucleus of the lateral geniculate body in the common shrew (Sorex araneus) and the bank vole (Clethrionomys glareolus): Golgi and Nissl studies

The topography and neuronal structure of the dorsal nucleus of the lateral geniculate body (GLd) of the common shrew and the bank vole are similar. The lateral geniculate body of both the species examined has a homogeneous structure and no observable cytoarchitectonic lamination. On the basis of the shape of the dendritic arbours as well as the pattern of dendritic arborisations the following two types of neurons were distinguished. Type I “bushy” neurons that have multipolar or round perikarya (common shrew perikarya 9–12 µm, bank vole perikarya 10–13 µm), with 4–6 short thick dendritic trunks that subdivide into many bush-like branches. The dendritic trunks are smooth, in contrast to the distal branches, which are covered with numerous spine-like protrusions of different lengths and forms. An axon emerges from the soma, sometimes very close to one of the primary dendrites. The type I neurons are typically projection cells that send their axons to the primary visual cortex. These neurons predominate in the GLd of both species. Type II neurons, which have an elongated soma with primary dendrites arising from opposite poles of the perikaryon (common shrew perikarya 8–10 µm, bank vole perikarya 9–11 µm). The dendritic arbours of these cells are less extensive and their dendrites have fewer spines than those of the type I neurons. Axons were seldom observed. The type II neurons are presumably interneurons and are definitely less numerous than the type I neurons

The nerve cells of the neostriatum in the common shrew (Sorex araneus) and bank vole (Clethrionomys glareolus): a Golgi comparative study

The studies were carried out on 12 brains derived from adult representatives of two mammalian orders, Insectivora and Rodentia. The neostriatum was compared in the common shrew (Sorex araneus) and bank vole (Clethrionomys glareolus). Three main types of striatal neuron were distinguished in the common shrew and five types of neurons in the bank vole. The fifth type of bank vole neurons was additionally divided into two subtypes with respect to dendritic pattern

Distribution of cocaine- and amphetamine-regulated transcript in the hippocampal formation of the guinea pig and domestic pig

This study provides a detailed description concerning the distribution of cocaineand amphetamine-regulated transcript (CART) subunits - CART61-102 and rhCART28-116 - in the hippocampal formation (HF) of the guinea pig and domestic pig, focussing on the dentate gyrus (DG) and hippocampus proper (HP). Although in both studied species CART-immunoreactive (CART-IR) neuronal somata and processes were present generally in the same layers, some species-specific differences were still found. In the granular layer (GL) of both species, the ovalshaped neurons and some thick varicose fibres were encountered. In the guinea pig there was an immunoreactive “band of dots”, probably representing crosssectioned terminals within the DG molecular layer (MOL), whereas in the domestic pig, some varicose fibres were detected, thus suggesting a different orientation of, at least, some nerve terminals. Furthermore, some CART-positive cells and fibres were observed in the hilus (HL) of the guinea pig, whereas in the analogical part of the domestic pig only nerve terminals were labelled. In both species, in the pyramidal layer (PL) of the hippocampus proper, CART-IR triangular somata were observed in the CA3 sector, as well as some positive processes in MOL; however, a few immunoreactive perikarya were found only in the CA1 sector of the guinea pig. As regards the localization patterns of two isoforms of CART in the guinea pig, both peptide fragments were present simultaneously in each of the labelled neurons or fibres, whereas in the domestic pig three types of fibres may be distinguished within the area of the DG. In the hilus and MOL of the dentate gyrus, there were fibres expressing both isoforms of CART in their whole length (fibres of the first type). Fibres of the second type (in GL) coexpressed both peptides only on their short segments, and the last ones (in MOL) expressed solely rhCART28-116. These results indicate that the distribution of the two CART isoforms are specifically related, thus the relationship between the two CART isoforms may imply different metabolic profiles of CART-expressing neurons

A morphometric comparative study of the lateral geniculate body in selected placental mammals: the common shrew, the bank vole, the rabbit, and the fox

The lateral geniculate body (LGN) was morphometrically examined and compared in representatives of four mammalian orders (Insectivora, Rodentia, Lagomorpha, and Carnivora). In each studied species, the lateral geniculate body was divided into two distinct parts: the dorsal nucleus (LGNd) and the ventral nucleus (LGNv). The lateral geniculate body of the common shrew and the bank vole are very similar in appearance and nuclear pattern. The dorsal and ventral nuclei of these two species also have the most similar statistical characteristics. The lateral geniculate body of the fox has the most complicated morphology and multilayered structure. A significant disproportion was observed between the sizes of both geniculate nuclei in the fox, where the dorsal nucleus definitely surpassed the ventral nucleus in terms of volume. With the exception of the fox, the neuronal density of the LGN nuclei was negatively correlated with the volumes of the LGN. The mean neuronal size of the LGNd and LGNv, which was the resultant of the length, width, area, and circumference of the soma, grew correlatively to the volumes of these nuclei. In all examined species, somas of the LGNd neurons are distinctly larger and have more similar shapes than the LGNv perikarya. In addition, the numerical density of neurons in the ventral nucleus is significantly higher than in the dorsal nucleus. All these morphometric parameters clearly differentiate the LGNd from the LGNv

The neuronal structure of the preoptic area in the mole and the rabbit: Golgi and Nissl studies

The present studies were carried out on the brains of the adult mole and rabbit. The preparations were made by means of the Golgi technique and the Nissl method. Two types of neurons were distinguished in the preoptic area (POA) of both species: bipolar and multipolar. The bipolar neurons have oval, fusiform or round perikarya and two dendritic trunks arising from the opposite poles of the cell body. The dendrites bifurcate once or twice. The dendritic branches have swellings, single spine-like and filiform processes. The multipolar neurons usually have triangular and quadrangular perikarya and from 3 to 5 dendritic trunks. The dendrites of the mole neurons branch sparsely, whereas the dendrites of the rabbit neurons display 2 or 3 divisions. On the dendritic branches varicosities and different protuberances were observed. The general morphology of the bipolar and multipolar neurons is similar in the mammals studied, although the neurons of the rabbit POA display a more complicated structure. Their dendritic branches show more divisions and possess more swellings and different processes than the dendrites of the neurons of the mole POA. Furthermore, of the multipolar neurons only the dendrites in POA of the rabbit were observed to have a rosary-like beaded appearance