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81.
E-Chiang Lee Urvi Desai Gennady Gololobov Seokjoo Hong Xiao Feng Xuan-Chuan Yu Jason Gay Nat Wilganowski Cuihua Gao Ling-Ling Du Joan Chen Yi Hu Sharon Zhao Laura Kirkpatrick Matthias Schneider Brian P. Zambrowicz Greg Landes David R. Powell William K. Sonnenburg 《The Journal of biological chemistry》2009,284(20):13735-13745
Angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4) are
secreted proteins that regulate triglyceride (TG) metabolism in part by
inhibiting lipoprotein lipase (LPL). Recently, we showed that treatment of
wild-type mice with monoclonal antibody (mAb) 14D12, specific for ANGPTL4,
recapitulated the Angptl4 knock-out (-/-) mouse phenotype of reduced
serum TG levels. In the present study, we mapped the region of mouse ANGPTL4
recognized by mAb 14D12 to amino acids
Gln29–His53, which we designate as specific
epitope 1 (SE1). The 14D12 mAb prevented binding of ANGPTL4 with LPL,
consistent with its ability to neutralize the LPL-inhibitory activity of
ANGPTL4. Alignment of all angiopoietin family members revealed that a sequence
similar to ANGPTL4 SE1 was present only in ANGPTL3, corresponding to amino
acids Glu32–His55. We produced a mouse mAb against
this SE1-like region in ANGPTL3. This mAb, designated 5.50.3, inhibited the
binding of ANGPTL3 to LPL and neutralized ANGPTL3-mediated inhibition of LPL
activity in vitro. Treatment of wild-type as well as hyperlipidemic
mice with mAb 5.50.3 resulted in reduced serum TG levels, recapitulating the
lipid phenotype found in Angptl3-/- mice. These results
show that the SE1 region of ANGPTL3 and ANGPTL4 functions as a domain
important for binding LPL and inhibiting its activity in vitro and
in vivo. Moreover, these results demonstrate that therapeutic
antibodies that neutralize ANGPTL4 and ANGPTL3 may be useful for treatment of
some forms of hyperlipidemia.Lipoprotein lipase
(LPL)5 plays a pivotal
role in lipid metabolism by catalyzing the hydrolysis of plasma triglycerides
(TGs). LPL is likely to be regulated by mechanisms that depend on nutritional
status and on the tissue in which it is expressed
(1–3).
Two secreted proteins, angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4
(ANGPTL4), play important roles in the regulation of LPL activity
(4,
5). ANGPTL3 and ANGPTL4 consist
of a signal peptide, an N-terminal segment containing coiled-coil domains, and
a C-terminal fibrinogen-like domain. The N-terminal segment as well as
full-length ANGPTL3 and ANGPTL4 have been shown to inhibit LPL activity, and
deletion of the N-terminal segment of ANGPTL3 and ANGPTL4 resulted in total
loss of LPL-inhibiting activity
(6,
7). These observations clearly
indicate that the N-terminal region of ANGPTL4 contains the functional domain
that inhibits LPL and affects plasma lipid levels. The coiled-coil domains
have been proposed to be responsible for oligomerization
(8); however, it is not known
whether the coiled-coil domains directly mediate the inhibition of LPL
activity.To define the physiological role of ANGPTL4 more clearly, we characterized
the pharmacological consequences of ANGPTL4 inhibition in mice treated with
the ANGPTL4-neutralizing monoclonal antibody (mAb) 14D12
(9). Injection of mAb 14D12
significantly lowered fasting TG levels in C57BL/6J mice relative to levels in
C57BL/6J mice treated with an isotype-matched anti-KLH control (KLH) mAb
(9). These reduced TG values
were similar to decreases in fasting plasma TG levels measured in
Angptl4 knock-out (-/-) mice. This study demonstrated that mAb 14D12
is a potent ANGPTL4-neutralizing antibody that is able to inhibit systemic
ANGPTL4 activity and thereby recapitulate the reduced lipid phenotype found in
Angptl4-/- mice. The readily apparent pharmacological
effect of mAb 14D12 prompted new questions about the epitope recognized by mAb
14D12 and how this antibody-antigen binding event affected ANGPTL4 function as
an LPL inhibitor.Although ANGPTL4 is able to interact directly with LPL
(10), it is not clear which
amino acids within ANGPTL4 mediate this interaction. Here we show that amino
acids Gln29–His53 of mANGPTL4 contain the epitope
for mAb 14D12. This region, hereby designated specific epitope 1 (SE1), also
defines a domain that mediates the interaction between ANGPTL4 and LPL and the
subsequent inactivation of LPL. With this information we present evidence that
ANGPTL3 also contains an SE1 region, and with antibodies specifically reactive
with ANGPTL3 SE1 we examine whether the ANGPTL3 SE1 region is involved in LPL
binding and inhibition. We also determined whether treatment of C57BL/6 mice
with an anti-ANGPTL3 SE1 mAb can recapitulate the phenotype of lower serum TG
and cholesterol levels found in Angptl3-/- mice. Finally
we tested the therapeutic potential of an anti-ANGPTL3 SE1 mAb for treatment
of hyperlipidemia in apolipoprotein E-/-
(ApoE-/-) or low density lipoprotein
receptor-/- (LDLr-/-) mice. 相似文献
82.
David Wunschel Bobbie-Jo Webb-Robertson Charles W. Frevert Shawn Skerrett Nat Beagley Alan Willse Heather Colburn Kathryn Antolick 《PloS one》2009,4(9)
The identification of biosignatures of aerosol exposure to pathogens has the potential to provide useful diagnostic information. In particular, markers of exposure to different types of respiratory pathogens may yield diverse sets of markers that can be used to differentiate exposure. We examine a mouse model of aerosol exposure to known Gram negative bacterial pathogens, Francisella tularensis novicida and Pseudomonas aeruginosa. Mice were subjected to either a pathogen or control exposure and bronchial alveolar lavage fluid (BALF) was collected at four and twenty four hours post exposure. Small protein and peptide markers within the BALF were detected by matrix assisted laser desorption/ionization (MALDI) mass spectrometry (MS) and analyzed using both exploratory and predictive data analysis methods; principle component analysis and degree of association. The markers detected were successfully used to accurately identify the four hour exposed samples from the control samples. This report demonstrates the potential for small protein and peptide marker profiles to identify aerosol exposure in a short post-exposure time frame. 相似文献
83.
Milhazes N Calheiros R Marques MP Garrido J Cordeiro MN Rodrigues C Quinteira S Novais C Peixe L Borges F 《Bioorganic & medicinal chemistry》2006,14(12):4078-4088
A multidisciplinary project was developed, combining the synthesis of a series of beta-nitrostyrene derivatives and the determination of their physicochemical parameters (redox potentials, partition coefficients), to the evaluation of the corresponding antibacterial activity. A complete conformational analysis was also performed, in order to get relevant structural information. Subsequently, a structure-property-activity (SPAR) approach was applied, through linear regression analysis, aiming at obtaining a putative correlation between the physicochemical parameters of the compounds investigated and their antibacterial activity (both against standard strains and clinical isolates). The beta-nitrostyrene compounds displayed a lower activity towards all the tested bacteria relative to the beta-methyl-beta-nitrostyrene analogues. This was observed particularly for the 3-hydroxy-4-methoxy-beta-methyl-beta-nitrostyrene (IVb) against the Gram-positive bacteria (Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium). The SPAR results revealed the existence of a clear correlation between the redox potentials and the antibacterial activity of the series of beta-nitrostyrene derivatives under study. 相似文献
84.
Martínková N Bačkor P Bartonička T Blažková P Cervený J Falteisek L Gaisler J Hanzal V Horáček D Hubálek Z Jahelková H Kolařík M Korytár L Kubátová A Lehotská B Lehotský R Lučan RK Májek O Matějů J Rehák Z Šafář J Tájek P Tkadlec E Uhrin M Wagner J Weinfurtová D Zima J Zukal J Horáček I 《PloS one》2010,5(11):e13853
Background
White-nose syndrome is a disease of hibernating insectivorous bats associated with the fungus Geomyces destructans. It first appeared in North America in 2006, where over a million bats died since then. In Europe, G. destructans was first identified in France in 2009. Its distribution, infection dynamics, and effects on hibernating bats in Europe are largely unknown.Methodology/Principal Findings
We screened hibernacula in the Czech Republic and Slovakia for the presence of the fungus during the winter seasons of 2008/2009 and 2009/2010. In winter 2009/2010, we found infected bats in 76 out of 98 surveyed sites, in which the majority had been previously negative. A photographic record of over 6000 hibernating bats, taken since 1994, revealed bats with fungal growths since 1995; however, the incidence of such bats increased in Myotis myotis from 2% in 2007 to 14% by 2010. Microscopic, cultivation and molecular genetic evaluations confirmed the identity of the recently sampled fungus as G. destructans, and demonstrated its continuous distribution in the studied area. At the end of the hibernation season we recorded pathologic changes in the skin of the affected bats, from which the fungus was isolated. We registered no mass mortality caused by the fungus, and the recorded population decline in the last two years of the most affected species, M. myotis, is within the population trend prediction interval.Conclusions/Significance
G. destructans was found to be widespread in the Czech Republic and Slovakia, with an epizootic incidence in bats during the most recent years. Further development of the situation urgently requires a detailed pan-European monitoring scheme. 相似文献85.
Differences in sperm morphology in foam‐nesting leptodactyline frogs (Anura,Leptodactylidae)
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Sperm morphology is diverse among vertebrates and is influenced by the reproductive strategies adopted by species. In anurans, sperm morphology is associated with reproductive modes and mating systems. Here, we describe the sperm morphology of 11 frog species in the genus Leptodactylus and that of Lithodytes lineatus and discuss the relationship between sperm morphology and species' mating systems. We observed two distinct sperm morphotypes among the leptodactyline species, which differed mostly in head morphology. Type I sperm had triangular head, discrete acrosome vesicle with posterior margin not clearly visible; type II sperm had elongated head, clear acrosomal vesicle with posterior margin clearly visible. These sperm types do not seem to be associated with phylogeny; instead, type II sperm was observed in all polyandrous species analysed and in species with evidences of polyandry. Moreover, sperm of all species presented tail with undulating membrane connected to the axial fibre. We suggest that differences in sperm morphology might be associated with sperm competition to what polyandrous species are subjected. However, natural history observations on polyandrous mating in some species presenting type II sperm and phylogenetic comparative studies are need to elucidate the role of mating systems in the evolution of sperm morphology in leptodactylines. 相似文献
86.
Tóthová L Hodosy J Kamodyová N Janega P Slobodníková L Liptáková A Boor P Celec P 《Current microbiology》2011,62(6):1739-1742
The role of innate immunity in the prevention of urinary tract infection is well-documented. Toll-like receptor 4 (TLR4) is
a major determinant of innate immune response. In an animal model of urinary tract infection, bactofection-mediated gene transfer
of TLR4 was tested in a preventive approach. Bactofection with TLR4 reduced the colonization with uropathogenic Escherichia
coli by 91% in the kidney and by 41% in the bladder. Reduced colonization was associated with lower oxidative stress and expression
of monocyte chemoattractant protein-1 and myeloperoxidase in the kidney. Bactofection with TLR4 was successful in the prevention
of ascending pyelonephritis. Further studies should focus on long-term effects, the dose response and the potential therapeutic
use in models of chronic urinary tract infection. 相似文献
87.
AimsCardiac glycosides have been extensively used in the treatment of congestive heart failure for more than 200 years. Recently, cardenolides and bufadienolides were isolated from mammalian tissue and are considered as a new class of steroidal hormones. The aim of the present work was to characterize the interaction between the most clinical used cardiac glycoside digoxin and the cardiac glycosides known to exist endogenously, i.e., ouabain, marinobufagin and telocinobufagin, on human kidney Na+/K+-ATPase.Main methodsInhibition of Na+/K+-ATPase activity from crude membrane preparations of human kidney was performed using increasing concentrations of the drugs alone or mixtures of ouabain:digoxin, telocinobufagin:digoxin and marinobufagin:digoxin in a fixed ratio 1:4, 2:3 and 3:2, respectively. The colorimetric method of Fiske and Subbarow was used to measure the inorganic phosphate released.Key findingsAnalyses of inhibition curves showed that the experimental curves for all combinations were superimposed on the theoretical additive curves indicating that an additive effect occurs among distinct cardenolides and bufadienolides combinations on the human α1β1 Na+/K+-ATPase protomer.SignificanceConsidering the extensive use of digoxin in the treatment of heart failure and the recent findings that endogenous cardiac glycosides may have altered levels in many diseases, including heart failure, the demonstration of additive effect between cardiac glycosides can help in the understanding of recent clinical observations, including that lower than usual doses of cardiac glycosides are necessary for decreasing mortality in these patients. 相似文献
88.
Sadeyen JR Trotereau J Velge P Marly J Beaumont C Barrow PA Bumstead N Lalmanach AC 《Microbes and infection / Institut Pasteur》2004,6(14):1278-1286
Asymptomatic Salmonella enterica serovar Enteritidis carrier state in poultry has serious consequences on food safety and public health due to the risks of food poisoning following consumption of contaminated products. An understanding the mechanisms of persistence of Salmonella in the digestive tract of chicken can be achieved by a better knowledge of the defects in the control of infection in susceptible versus resistant animals. The gene expression of innate immune response factors including anti-microbial molecules, inflammatory and anti-infectious cytokines was studied in the caecal lymphoid tissue associated with the carrier state. Expression levels of these genes were assessed by real-time PCR and were compared in two inbred lines of chickens differing in resistance to the carrier state following oral inoculation of S. enterica serovar Enteritidis at 1 week of age. No correlation was observed between resistance/susceptibility to caecal carrier state and level of interleukin (IL)-1beta, IL-8, IL-18, inducible NO synthase (iNOS) and natural resistance associated macrophage protein 1 (NRAMP1). A high baseline level of defensin gene expression was recorded in young animals from the susceptible line. In contrast, a significantly low expression of interferon-gamma (IFN-gamma) gene was observed in these susceptible infected animals in comparison to resistant ones and healthy counterparts. IFN-gamma expression level represents a valuable indication of immunodeficiency associated with persistence of Salmonella in the chicken digestive tract, and IFN-gamma thus represents a factor to consider in the development of prophylactic measures for the reduction of Salmonella carrier state. 相似文献
89.
Natália Assaife-Lopes Vasco C. Sousa Daniela B. Pereira Joaquim A. Ribeiro Ana M. Sebastião 《Purinergic signalling》2014,10(2):251-267
Brain-derived neurotrophic factor (BDNF) signalling is critical for neuronal development and transmission. Recruitment of TrkB receptors to lipid rafts has been shown to be necessary for the activation of specific signalling pathways and modulation of neurotransmitter release by BDNF. Since TrkB receptors are known to be modulated by adenosine A2A receptor activation, we hypothesized that activation of A2A receptors could influence TrkB receptor localization among different membrane microdomains. We found that adenosine A2A receptor agonists increased the levels of TrkB receptors in the lipid raft fraction of cortical membranes and potentiated BDNF-induced augmentation of phosphorylated TrkB levels in lipid rafts. Blockade of the clathrin-mediated endocytosis with monodansyl cadaverine (100 μM) did not modify the effects of the A2A receptor agonists, but significantly impaired BDNF effects on TrkB recruitment to lipid rafts. The effect of A2A receptor activation in TrkB localization was mimicked by 5 μM forskolin, an adenylyl cyclase activator. Also, it was blocked by the PKA inhibitors Rp-cAMPs and PKI-(14-22) and by the Src-family kinase inhibitor PP2. Moreover, removal of endogenous adenosine or disruption of lipid rafts reduced BDNF stimulatory effects on glutamate release from cortical synaptosomes. Lipid raft integrity was also required for the effects of BDNF upon hippocampal long-term potentiation at CA1 synapses. Our data demonstrate, for the first time, a BDNF-independent recruitment of TrkB receptors to lipid rafts, induced by the activation of adenosine A2A receptors, with functional consequences for TrkB phosphorylation and BDNF-induced modulation of neurotransmitter release and hippocampal plasticity. 相似文献
90.
Natália Salazar Mónica Marcela Castiblanco-Valencia Ludmila Bezerra da Silva íris Arantes de Castro Denize Monaris Hana Paula Masuda Angela Silva Barbosa Ana Paula Mattos Arêas 《PloS one》2014,9(11)
Infections caused by Staphylococcus aureus – particularly nosocomial infections - represent a great concern. Usually, the early stage of pathogenesis consists on asymptomatic nasopharynx colonization, which could result in dissemination to other mucosal niches or invasion of sterile sites, such as blood. This pathogenic route depends on scavenging of nutrients as well as binding to and disrupting extracellular matrix (ECM). Manganese transport protein C (MntC), a conserved manganese-binding protein, takes part in this infectious scenario as an ion-scavenging factor and surprisingly as an ECM and coagulation cascade binding protein, as revealed in this work. This study showed a marked ability of MntC to bind to several ECM and coagulation cascade components, including laminin, collagen type IV, cellular and plasma fibronectin, plasminogen and fibrinogen by ELISA. The MntC binding to plasminogen appears to be related to the presence of surface-exposed lysines, since previous incubation with an analogue of lysine residue, ε-aminocaproic acid, or increasing ionic strength affected the interaction between MntC and plasminogen. MntC-bound plasminogen was converted to active plasmin in the presence of urokinase plasminogen activator (uPA). The newly released plasmin, in turn, acted in the cleavage of the α and β chains of fibrinogen. In conclusion, we describe a novel function for MntC that may help staphylococcal mucosal colonization and establishment of invasive disease, through the interaction with ECM and coagulation cascade host proteins. These data suggest that this potential virulence factor could be an adequate candidate to compose an anti-staphylococcal human vaccine formulation. 相似文献