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51.
K Polireddy MM Khan H Chavan S Young X Ma A Waller M Garcia D Perez S Chavez JJ Strouse MK Haynes CG Bologa TI Oprea GP Tegos LA Sklar P Krishnamurthy 《PloS one》2012,7(7):e40005
ABCB6 is a member of the adenosine triphosphate (ATP)-binding cassette family of transporter proteins that is increasingly recognized as a relevant physiological and therapeutic target. Evaluation of modulators of ABCB6 activity would pave the way toward a more complete understanding of the significance of this transport process in tumor cell growth, proliferation and therapy-related drug resistance. In addition, this effort would improve our understanding of the function of ABCB6 in normal physiology with respect to heme biosynthesis, and cellular adaptation to metabolic demand and stress responses. To search for modulators of ABCB6, we developed a novel cell-based approach that, in combination with flow cytometric high-throughput screening (HTS), can be used to identify functional modulators of ABCB6. Accumulation of protoporphyrin, a fluorescent molecule, in wild-type ABCB6 expressing K562 cells, forms the basis of the HTS assay. Screening the Prestwick Chemical Library employing the HTS assay identified four compounds, benzethonium chloride, verteporfin, tomatine hydrochloride and piperlongumine, that reduced ABCB6 mediated cellular porphyrin levels. Validation of the identified compounds employing the hemin-agarose affinity chromatography and mitochondrial transport assays demonstrated that three out of the four compounds were capable of inhibiting ABCB6 mediated hemin transport into isolated mitochondria. However, only verteporfin and tomatine hydrochloride inhibited ABCB6's ability to compete with hemin as an ABCB6 substrate. This assay is therefore sensitive, robust, and suitable for automation in a high-throughput environment as demonstrated by our identification of selective functional modulators of ABCB6. Application of this assay to other libraries of synthetic compounds and natural products is expected to identify novel modulators of ABCB6 activity. 相似文献
52.
53.
Olofsson PS Katz DA Rosas-Ballina M Levine YA Ochani M Valdés-Ferrer SI Pavlov VA Tracey KJ Chavan SS 《Molecular medicine (Cambridge, Mass.)》2012,18(1):539-543
The immune response to infection or injury coordinates host defense and tissue repair, but also has the capacity to damage host tissues. Recent advances in understanding protective mechanisms have found neural circuits that suppress release of damaging cytokines. Stimulation of the vagus nerve protects from excessive cytokine production and ameliorates experimental inflammatory disease. This mechanism, the inflammatory reflex, requires the α7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel expressed on macrophages, lymphocytes, neurons and other cells. To investigate cell-specific function of α7nAChR in the inflammatory reflex, we created chimeric mice by cross-transferring bone marrow between wild-type (WT) and α7nAChR-deficient mice. Deficiency of α7nAChR in bone marrow-derived cells significantly impaired vagus nerve-mediated regulation of tumor necrosis factor (TNF), whereas α7nAChR deficiency in neurons and other cells had no significant effect. In agreement with recent work, the inflammatory reflex was not functional in nude mice, because functional T cells are required for the integrity of the pathway. To investigate the role of T-cell α7nAChR, we adoptively transferred α7nAChR-deficient or WT T cells to nude mice. Transfer of WT and α7nAChR-deficient T cells restored function, indicating that α7nAChR expression on T cells is not necessary for this pathway. Together, these results indicate that α7nAChR expression in bone marrow-derived non-T cells is required for the integrity of the inflammatory reflex. 相似文献
54.
Sangeeta S Chavan LaQueta K Hudson Jian Hua Li Mahendar Ochani Yael Harris Nirav B Patel David Katz Joshua A Scheinerman Valentin A Pavlov Kevin J Tracey 《Molecular medicine (Cambridge, Mass.)》2012,18(1):1161-1168
Obesity is a major risk factor for insulin resistance, type 2 diabetes mellitus and cardiovascular disease. The pathophysiology of obesity is associated with chronic low-grade inflammation. Adipose tissue in obesity is significantly infiltrated by macrophages that secrete cytokines. The mechanisms of interaction between macrophages and adipocytes, leading to macrophage activation and increased cytokine release, remain to be elucidated. We reasoned that an adipocyte-derived factor might stimulate activation of macrophages. We have identified pigment epithelium-derived factor (PEDF) as a mediator of inflammation that is secreted by adipocytes and mediates macrophage activation. Recombinant PEDF activates macrophages to release tumor necrosis factor (TNF) and interleukin-1 (IL-1). The PEDF receptor adipose triglyceride lipase (ATGL) is required for PEDF-mediated macrophage activation. Selective inhibition of ATGL on macrophages attenuates PEDF-induced TNF production, and PEDF enhances the phosphorylation of p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases. PEDF administration to rats results in increased serum TNF levels, and insulin resistance. Together, these findings suggest that PEDF secreted by adipocytes contributes to the onset and maintenance of chronic inflammation in obesity, and may be a therapeutic target in ameliorating insulin resistance. 相似文献
55.
Seventy-eight soil samples were collected from the various locations in the vicinity of Kaziranga National Park (Assam), India, during April to October 2009 and screened for the presence of keratinophilic fungi using the hair baiting techniques for isolation. Thirty-nine isolates were recovered and identified by recognition of their macro- and micromorphological features. Their identification was also confirmed by the BLAST search of sequences of the ITS1-5.8S-ITS2 rDNA region against the NCBI/GenBank data and compared with deposited sequences for identification purpose. Eleven species related to seven genera were recorded viz. Aphanoascus durus (1.28%), Arthroderma tuberculatum (3.84%), Arthroderma corniculatum (1.28%), Chrysosporium indicum (16.66%), C. tropicum (3.84%), Ctenomyces serratus (5.12%), Keratinophyton punsolae (1.28%), Microsporum appendiculatum (1.28%), Microsporum gypseum complex (11.53%), Trichophyton mentagrophytes (11.28%) and T. terrestre (2.56%). 相似文献
56.
Moharekar S.T. Lokhande S.D. Hara T. Tanaka R. Tanaka A. Chavan P.D. 《Photosynthetica》2003,41(2):315-317
With the increase in concentration of applied salicylic acid (SA), chlorophyll (Chl) content decreased significantly in both
wheat and moong seedlings. Chl a/b ratio decreased significantly only in wheat and remained constant in moong. On the other hand, total carotenoid (Car) content,
size of xanthophyll pool, and de-epoxidation rate increased significantly with an increase in SA concentration in both plant
species. Hence SA treatment may induce Car biosynthesis in these plant species, but the increase in the xanthophyll pool and
de-epoxidation rate indicates that SA may create oxidative stress the degree of which is different in various plants.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献
57.
Dnyaneshwar Warude Preeti Chavan Kalpana Joshi Bhushan Patwardhan 《Plant Molecular Biology Reporter》2003,21(4):467-467
Current DNA isolation methods are limited in their ability to obtain quality and/or quantity DNA from plants, such asEmblica officinalis, Terminalia belerica, andTerminalia chebula, which have low pH and high amounts of secondary metabolites in tissue extracts. Our modified DNA isolation method yields
good-quality, high-molecular-weight DNA that is free of contaminants and colored pigments and is suitable for PCR amplification.
This method is also useful for isolating DNA from dry powders. 相似文献
58.
Summary
Sesbania showed a luxuriant growth in soil with an electrical conductivity of up to 10 m Scm−1. Under saline conditions Na and Cl accumulated at different rates in the plants. Accumulation of these ions in the leaf rachis
compared with leaflets appears to be an adaptive feature of this legume. Maintenance of an optimum K level and accumulation
of Ca are also indicative of a salt-tolerance mechanism. Accumulation of Fe in the roots of salt-stressed plants is noteworthy.
Organic acids and soluble sugars which accumulated in plants under stress condition may play a role in osmotic adjustment.
The level of proline, however, remained unaltered. Though the chlorophyll content of the leaves decreased, the photosynthetic
rate was found to be enhanced by saline conditions. The probable relationships between these changes and the salt tolerance
mechanism in the plant have been discussed. 相似文献
59.
Antigenic drift and shift involving the surface proteins of Influenza virus gave rise to new strains that caused epidemics affecting millions of people worldwide over the last hundred years. Variations in the membrane proteins like Hemagglutinin (HA) and Neuraminidase (NA) necessitates new vaccine strains to be updated frequently and poses challenge to effective vaccine design. Though the HA protein, the primary target of the human immune system, has been well studied, reports on the antigenic variability in the other membrane protein NA are sparse. In this paper we investigate the molecular basis of antigenic drift in the NA protein of the Influenza A/H3N2 vaccine strains between 1968 and 2009 and proceed to establish correlation between antigenic drift and antigen-antibody interactions. Sequence alignments and phylogenetic analyses were carried out and the antigenic variability was evaluated in terms of antigenic distance. To study the effects of antigenic drift on the protein structures, 3D structure of NA from various strains were predicted. Also, rigid body docking protocol has been used to study the interactions between these NA proteins and antibody Mem5, a 1998 antibody. 相似文献
60.
Reeves PM Bommarius B Lebeis S McNulty S Christensen J Swimm A Chahroudi A Chavan R Feinberg MB Veach D Bornmann W Sherman M Kalman D 《Nature medicine》2005,11(7):731-739
The Poxviridae family members vaccinia and variola virus enter mammalian cells, replicate outside the nucleus and produce virions that travel to the cell surface along microtubules, fuse with the plasma membrane and egress from infected cells toward apposing cells on actin-filled membranous protrusions. We show that cell-associated enveloped virions (CEV) use Abl- and Src-family tyrosine kinases for actin motility, and that these kinases act in a redundant fashion, perhaps permitting motility in a greater range of cell types. Additionally, release of CEV from the cell requires Abl- but not Src-family tyrosine kinases, and is blocked by STI-571 (Gleevec), an Abl-family kinase inhibitor used to treat chronic myelogenous leukemia in humans. Finally, we show that STI-571 reduces viral dissemination by five orders of magnitude and promotes survival in infected mice, suggesting possible use for this drug in treating smallpox or complications associated with vaccination. This therapeutic approach may prove generally efficacious in treating microbial infections that rely on host tyrosine kinases, and, because the drug targets host but not viral molecules, this strategy is much less likely to engender resistance compared to conventional antimicrobial therapies. 相似文献