1.
Extinction of Tumor Antigen Expression by SF2/ASF in JCV-Transformed Cells.
Source
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA, USA.
Abstract
The human neurotropic polyomavirus JC (JCV) induces a broad range of neural-origin tumors in experimental animals and has been repeatedly detected in several human cancers, most notably neural crest-origin tumors including medulloblastomas and glioblastomas. The oncogenic activity of JCV is attributed to the viral early gene products, large T and small t antigens, as evident by results from in vitro cell culture and in vivo animal studies. Recently, we have shown that alternative splicing factor, SF2/ASF, has the capacity to exert a negative effect on transcription and splicing of JCV genes in glial cells through direct association with a specific DNA motif within the viral promoter region. Here, we demonstrate that SF2/ASF suppresses large T antigen expression in JCV-transformed tumor cell lines, and the expression of SF2/ASF in such tumor cells thereby inhibits the transforming capacity of the viral tumor antigens. Moreover, down-regulation of SF2/ASF in viral-transformed tumor cell lines induces growth and proliferation of the tumor cells. Mapping analysis of the minimal peptide domain of SF2/ASF responsible for JCV promoter silencing and tumor suppressor activity suggests that amino acid residues 76 to 100 of SF2/ASF are functionally sufficient to suppress the growth of the tumor cells. These observations demonstrate a role for SF2/ASF in JCV-mediated cellular transformation and provide a new avenue of research to pathogenic mechanisms of JCV-induced tumors.
- PMID:
- 22207898
- [PubMed - in process]
Regulation of adipocyte formation by GLP-1/GLP-1R signalling.
Source
ETH Zuerich, Switzerland;
Abstract
Increased nutrient intake leads to excessive adipose tissue accumulation, obesity and the development of associated metabolic disorders. How the intestine signals to adipose tissue to adapt to increased nutrient intake, however, is still not completely understood. We show here, that the gut peptide GLP-1 or its long-lasting analogue liraglutide, function as intestinally derived signals to induce adipocyte formation, both in vitro and in vivo. GLP-1 and liraglutide activate the GLP-1R, thereby promoting pre-adipocyte pro-liferation and inhibition of apoptosis. This is achieved at least partly through activation of ERK, PKC and AKT signaling pathways. In contrast, loss of GLP-1R expression causes reduction in adipogenesis, through induction of apoptosis in pre-adipocytes, by inhibition of the above mentioned pathways. Since GLP-1 and liraglutide are used for the treatment of type 2 diabetes, these findings implicate GLP-1 as a regulator of adipogenesis, which could be an alternate pathway leading to improved lipid homeostasis and controlled downstream insulin signaling.
Productive recognition of factor IX by factor XIa exosites requires disulfide linkage between heavy and light chains of factor XIa.
Source
Temple University, United States.
Abstract
In the intrinsic pathway of blood coagulation factor XIa (FXIa) activates factor IX (FIX) by cleaving the zymogen at Arg145-Ala146 and Arg180-Val181 bonds releasing an 11 kDa activation peptide. FXIa and its isolated light chain (FXIa-LC) cleave S-2366 at comparable rates, but FXIa-LC is a very poor activator of FIX, possibly because FIX undergoes allosteric modification on binding to an exosite on the heavy chain of FXIa (FXIa-HC) required for optimal cleavage rates of the two scissile bonds of FIX. However preincubation of FIX with a saturating concentration of isolated FXIa-HC did not result in any potentiation in the rate of FIX cleavage by FXIa-LC. Furthermore, if FIX binding via the heavy chain exosite of FXIa determines the affinity of the enzyme-substrate interaction then the isolated FXIa-HC should inhibit the rate of FIX activation by depleting the substrate. However, whereas FXIa/S557A inhibited FIX activation of by FXIa, FXIa-HC did not. Therefore, we examined FIX binding to FXIa/S557A, FXIa-HC, FXIa-LC, FXIa/C362S/C482S and FXIa/S557A/C362S/C482S. The heavy and light chains are disulfide linked in FXIa/S557A but not in FXIa/C362S/C482S and FXIa/S557A/C362S/C482S. In an ELISA assay only FXI/S557A ligated FIX with high affinity. Partial reduction of FXIa/S557A to produce heavy and light chains resulted in decreased FIX binding, and this function was regained upon reformation of the disulfide linkage between the heavy and the light chains. We therefore conclude that substrate recognition by the FXIa exosite(s) requires disulfide-linked heavy and light chains.
Vascular Bioactivation of Nitroglycerin Is Catalyzed by Cytosolic Aldehyde Dehydrogenase-2.
Source
Department of Pharmacology and Toxicology, Karl-Franzens Universität Graz, Graz, Austria; Institute of Molecular Biosciences, Karl-Franzens Universität Graz, Graz, Austria; Division of Cardiology, Medical University Graz, Austria.
Abstract
Rationale:According to general view, aldehyde dehydrogenase-2 (ALDH2) catalyzes the high-affinity pathway of vascular nitroglycerin (GTN) bioactivation in smooth muscle mitochondria. Despite having wide implications to GTN pharmacology and raising many questions that are still unresolved, mitochondrial bioactivation of GTN in blood vessels is still lacking experimental support.Objective:In the present study, we investigated whether bioactivation of GTN is affected by the subcellular localization of ALDH2 using immortalized ALDH2-deficient aortic smooth muscle cells and mouse aortas with selective overexpression of the enzyme in either cytosol or mitochondria.Methods and Results:Quantitative Western blotting revealed that ALDH2 is mainly cytosolic in mouse aorta and human coronary arteries, with only approximately 15% (mouse) and approximately 5% (human) of the enzyme being localized in mitochondria. Infection of ALDH2-deficient aortic smooth muscle cells or isolated aortas with adenovirus containing ALDH2 cDNA with or without the mitochondrial signal peptide sequence led to selective expression of the protein in mitochondria and cytosol, respectively. Cytosolic overexpression of ALDH2 restored GTN-induced relaxation and GTN denitration to wild-type levels, whereas overexpression in mitochondria (6-fold vs wild-type) had no effect on relaxation. Overexpression of ALDH2 in the cytosol of ALDH2-deficient aortic smooth muscle cells led to a significant increase in GTN denitration and cyclic GMP accumulation, whereas mitochondrial overexpression had no effect.Conclusions:The data indicate that vascular bioactivation of GTN is catalyzed by cytosolic ALDH2. Mitochondrial GTN metabolism may contribute to oxidative stress-related adverse effects of nitrate therapy and the development of nitrate tolerance.
Investigating the Neural Correlates of Pathological Cortical Networks in Alzheimer's Disease using Heterogeneous Neuronal Models.
Abstract
This paper describes an investigation into the pathophysiological causes of abnormal cortical oscillations in Alzheimer's disease (AD) using two heterogeneous neuronal network models. The effect of excitatory circuit disruption on the beta band power (13-30 Hz) using a conductance-based network model of 200 neurons is assessed. Then, the neural correlates of abnormal cortical oscillations in different frequency bands based on a larger network model of 1000 neurons consisting of different types of cortical neurons is also analyzed. Electroencephalography (EEG) studies in AD patients have shown that beta band power (13-30 Hz) decreased in the early stages of the disease with a parallel increase in theta band power (4-7 Hz). This abnormal change progresses with the later stages of the disease but with decreased power spectra in other fast frequency bands plus an increase in delta band power (1-3 Hz). Our results show that, despite the heterogeneity of the network models, the beta band power is significantly affected by excitatory neural and synaptic loss. Secondly, the results of modeling a functional impairment in the excitatory circuit shows that beta band power exhibits the most decrease compared with other bands. Previous biological experiments on different types of cultural excitatory neurons show that cortical neuronal death is mediated by dysfunctional ionic behavior that might specifically contribute to the pathogenesis of β-amyloid peptide (Aβ)-induced neuronal death in AD. Our study also shows that beta band power was the first affected component when the modeled excitatory circuit begins to lose neurons and synapses.
Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells.
Source
Department of Molecular Microbiology and Immunology, Bioinformatics Core, Norris Comprehensive Cancer Center at University of Southern California Epigenome Center and Division of Hematology, and Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033.
Abstract
Misregulation of a pluripotency-associated transcription factor network in adult tissues is associated with the expansion of rare, highly malignant tumor-initiating stem cells (TISCs) through poorly understood mechanisms. We demonstrate that robust and selective expression of the receptor for the adipocyte-derived peptide hormone leptin (OB-R) is a characteristic feature of TISCs and of a broad array of embryonic and induced pluripotent stem cells and is mediated directly by the core pluripotency-associated transcription factors OCT4 and SOX2. TISCs exhibit sensitized responses to leptin, including the phosphorylation and activation of the pluripotency-associated oncogene STAT3 and induction of Oct4 and Sox2, thereby establishing a self-reinforcing signaling module. Exposure of cultured mouse embryonic stem cells to leptin sustains pluripotency in the absence of leukemia inhibitory factor. By implanting TISCs into leptin-deficient ob/ob mice or into comparably overweight Lepr(db/db) mice that produce leptin, we provide evidence of a central role for the leptin-TISC-signaling axis in promoting obesity-induced tumor growth. Differential responses to extrinsic, adipocyte-derived cues may promote the expansion of tumor cell subpopulations and contribute to oncogenesis.
Dissociation Chemistry of Hydrogen-Deficient Radical Peptide Anions.
Source
Department of Chemistry, University of California, Riverside, CA, 92521, USA.
Abstract
The fragmentation chemistry of anionic deprotonated hydrogen-deficient radical peptides is investigated. Homolytic photodissociation of carbon-iodine bonds with 266 nm light is used to generate the radical species, which are subsequently subjected to collisional activation to induce further dissociation. The charges do not play a central role in the fragmentation chemistry; hence deprotonated peptides that fragment via radical directed dissociation do so via mechanisms which have been reported previously for protonated peptides. However, charge polarity does influence the overall fragmentation of the peptide. For example, the absence of mobile protons favors radical directed dissociation for singly deprotonated peptides. Similarly, a favorable dissociation mechanism initiated at the N-terminus is more notable for anionic peptides where the N-terminus is not protonated (which inhibits the mechanism). In addition, collisional activation of the anionic peptides containing carbon-iodine bonds leads to homolytic cleavage and generation of the radical species, which is not observed for protonated peptides presumably due to competition from lower energy dissociation channels. Finally, for multiply deprotonated radical peptides, electron detachment becomes a competitive channel both during the initial photoactivation and following subsequent collisional activation of the radical. Possible mechanisms that might account for this novel collision-induced electron detachment are discussed.
Vasoactive Intestinal Peptide Enhances TNF-α-Induced IL-6 and IL-8 Synthesis in Human Proximal Renal Tubular Epithelial Cells by NF-κB-Dependent Mechanism.
Source
Division of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Abstract
Vasoactive intestinal polypeptide (VIP) is a 28-amino acid neuropeptide with vasodilator, bronchodilator, and anti-inflammatory effects. But little is known about its pro-inflammatory effects. We investigated the effect of VIP on the secretion of interleukin-6 (IL-6) and interleukin-8 (IL-8), two pro-inflammatory cytokines, in TNF-α-activated proximal renal tubular epithelial cell line (HK-2 cells). Cultured HK-2 cells were treated with TNF-α in the presence or absence of VIP with a dose range from 1 to 100 nM, followed by analysis of pro-inflammatory cytokines (IL-6 and IL-8) induction and their signal events including activation of the NF-κB pathway. We report here that tumor necrosis factor-α (TNF-α) increased IL-6 and IL-8 production, and that these effects were potentiated by VIP at 10 nM in HK-2 cells. However, VIP at 1 and 100 nM did not display this function. Consistent with these observations, we were able to show that VIP at 10 nM upregulated TNF-α-induced phosphorylation of IκB-α, leading to IκB-α degradation and the subsequent nuclear translocation of NF-κB. Furthermore, VIP-enhanced activation of NF-κB transcription activity was demonstrated using a NF-κB reporter construct upon transient transfection into HK-2 cells. These results strongly suggest that VIP synergistically enhances TNF-α-stimulated IL-6 and IL-8 synthesis via activating the NF-κB pathway in HK-2 cells.
An ELISA based on the repeated foot-and-mouth disease virus 3B epitopepeptide can distinguish infected and vaccinated cattle.
Source
College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
Abstract
To develop a strategy of differentiating infected from vaccinated animals (DIVA) with foot-and-mouth disease virus (FMDV), a short (27aa) peptide containing three conserved linear B cell epitopes of the FMDV 3B nonstructural protein was designed. This novel BF peptide was synthesized using a gene splicing by overlap extension protocol with preferred codons for Escherichia coli. The resultant eight tandem repeat multimer (1, 2, 4, 6, 8, 16, 24, and 32BF) were expressed as soluble fusion proteins in E. coli. An indirect ELISA was developed based on the recombinant 8BF protein with the aim of specifically distinguishing antibodies induced by FMDV infection but not those induced by vaccination. Using the cut-off value of 0.3, the sensitivity of the assay was 96.8% and the specificities for naive and vaccinated cattle were 99.8 and 99.0%, respectively. The performance of the newly developed epitope-based ELISA was compared with three commercial NSP ELISA kits. The 8BF-ELISA appears to be a promising DIVA test for FMD control and eradication.
Selection of a whole-cell biocatalyst for methyl parathion biodegradation.
Source
Taishan University, Shandong, 271021, China.
Abstract
Whole-cell biocatalyst has the potential to become a cost-effective alternative to conventional enzyme methods for solving ecological and energy issues. However, cytosolic-expressing biocatalyst systems are critically disadvantaged due to the low permeability of the cell membrane. To overcome substrate transport barrier, periplasmic secretion and surface display biocatalysts were developed by expressing signal peptides or anchor proteins in Escherichia coli. In this work, six carriers were compared in regard to whole-cell activity of methyl parathion hydrolase (MPH). Our results indicate that the surface display systems yielded one to three times whole-cell activity than the periplasmic secretion systems. Although periplasmic secretion systems showed generally more stable than surface display systems, surface display appeared more suitable for whole-cell biocatalyst. It should note that the applicability of the DsbA/PhoA/AIDA-I leader to MPH expression is shown here for the first time. In addition, the result provided a useful reference for other whole-cell biocatalyst selection.
Evidence for a new post-translational modification in Staphylococcus aureus: Hydroxymethylation of asparagine and glutamine.
Source
Protein Analysis Facility, University of Lausanne, 1015 Lausanne, Switzerland.
Abstract
Staphylococcus aureus is an opportunistic pathogen whose infectious capacity depends on surface proteins, which enable bacteria to colonize and invade host tissues and cells. We analyzed "trypsin-shaved" surface proteins of S. aureus cultures by high resolution LC-MS/MS at different growth stages and culture conditions. Some modified peptideswere identified, with a mass shift corresponding to the addition of a CH(2)O group (+30.0106u). We present evidence that this shift corresponds to a hyxdroxymethylation of asparagine and glutamine residues. This known but poorly documented post-translational modification was only found in a few proteins of S. aureus grown under specific conditions. This specificity seemed to exclude the hypothesis of an artifact due to sample preparation. Altogether hydroxymethylation was observed in 35 peptides from 15 proteins in our dataset, which corresponded to 41 modified sites, 35 of them being univocally localized. While no function can currently be assigned to this post-translational modification, we hypothesize that it could be linked to modulation of virulence factors, since it was mostly found on some surface proteins of S. aureus.
Copyright © 2011. Published by Elsevier B.V.
Sensitivity of Amyloid Formation by Human Islet Amyloid Polypeptide to Mutations at Residue 20.
Source
Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
Abstract
Islet amyloid polypeptide (IAPP, amylin) is responsible for amyloid formation in type 2 diabetes and in islet cell transplants. The only known natural mutation found in mature human IAPP is a Ser20-to-Gly missense mutation, found with small frequency in Chinese and Japanese populations. The mutation appears to be associated with increased risk of early-onset type 2 diabetes. Early measurements in the presence of organic co-solvents showed that S20G-IAPP formed amyloid more quickly than the wild type. We confirm that the mutant accelerates amyloid formation under a range of conditions including in the absence of co-solvents. Ser20 adopts a normal backbone geometry, and the side chain makes no steric clashes in models of IAPP amyloid fibers, suggesting that the increased rate of amyloid formation by the mutant does not result from the relief of steric incompatibility in the fiber state. Transmission electronic microscopy, circular dichroism, and seeding studies were used to probe the structure of the resulting fibers. The S20G-IAPP peptide is toxic to cultured rat INS-1 (transformed rat insulinoma-1) β-cells. The sensitivity of amyloid formation to the identity of residue 20 was exploited to design a variant that is much slower to aggregate and that inhibits amyloid formation by wild-type IAPP. An S20K mutant forms amyloid with an 18-fold longer lag phase. Thioflavin T binding assays, together with experiments using a p-cyanophenylalanine (p-cyanoPhe) variant of human IAPP, show that the designed S20K mutant inhibits amyloid formation by human IAPP. The experiments illustrate how p-cyanoPhe can be exploited to monitor amyloid formation even in the presence of other amyloidogenic proteins.
Copyright © 2011. Published by Elsevier Ltd.
Molecular Structure and Peptidoglycan Recognition of Mycobacterium tuberculosis ArfA (Rv0899).
Source
Sanford Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Abstract
Mycobacterium tuberculosis ArfA (Rv0899) is a membrane protein encoded by an operon that is required for supporting bacterial growth in acidic environments. Its C-terminal domain (C domain) shares significant sequence homology with the OmpA-like family of peptidoglycan-binding domains, suggesting that its physiological function in acid stress protection may be related to its interaction with the mycobacterial cell wall. Previously, we showed that ArfA forms three independently structured modules, and we reported the structure of its central domain (B domain). Here, we describe the high-resolution structure and dynamics of the C domain, and we identify ArfA as a peptidoglycan-binding protein and elucidate the molecular basis for its specific recognition of diaminopimelate-type peptidoglycan. The C domain of ArfA adopts the characteristic fold of the OmpA-like family. It exhibits pH-dependent conformational dynamics (with significant heterogeneity at neutral pH and a more ordered structure at acidic pH), which could be related to its acid stress response. The C domain associates tightly with polymeric peptidoglycan isolated from M. tuberculosis and also associates with a soluble peptide intermediate of peptidoglycan biosynthesis. This enabled us to characterize the peptidoglycan binding site where five highly conserved ArfA residues, including two key arginines, establish the specificity for diaminopimelate- but not Lys-type peptidoglycan. ArfA is the first peptidoglycan-binding protein to be identified in M. tuberculosis. Its functions in acid stress protection and peptidoglycan binding suggest a link between the acid stress response and the physicochemical properties of the mycobacterial cell wall.
Copyright © 2011. Published by Elsevier Ltd.
Postprandial plasma PYY concentrations are associated with increased regional gray matter volume and rCBF declines in caudate nuclei - A combined MRI and H(2)(15)O PET study.
Source
Obesity and Diabetes Clinical Research Section, NIDDK-NIH, DHHS, Phoenix, AZ, USA.
Abstract
The anorexigenic gastrointestinal hormone Peptide YY plays an important role in the communication between the gastrointestinal tract and the central nervous system. PYY has been shown to modulate brain activity in regions implicated in reward and food related behavior. Its effects on brain structure however, remain unknown. Voxel-based morphometry was used to investigate the relationship between fasting and postprandial plasma PYY concentrations and regional gray matter volume (GMV). For this analysis twenty adult, non diabetic Caucasians were included (18F/2M, age 31±9y, percentage of body fat [PFAT] 32±8%) who had volumetric brain magnetic resonance images and underwent H(2)(15)O positron emission tomographic (PET) measurements of regional cerebral blood flow (rCBF), a marker of local neuronal activity, and measurements of plasma total PYY, prior to (fasting) and following a satiating liquid meal. Voxel-wise analysis revealed a regional positive association between postprandial PYY and gray matter volume bilaterally in the caudate nuclei. These associations remained significant (p<0.05) after small volume correction for multiple comparisons. Based on these findings we investigated whether postprandial PYY is associated with PET measured rCBF of the caudate nucleus. We found a significant negative association between average postprandial caudate rCBF and postprandial plasma PYY concentrations (r=-0.60, p<0.02, age, sex and PFAT adjusted). Average postprandial caudate rCBF was also negatively associated with rCBF in the right medial orbitofrontal cortex and the right hippocampal formation (p<0.05, corrected for multiple comparisons). Total PYY is positively associated with gray matter but negatively with postprandial activity in the caudate nuclei while caudate activity is negatively associated with rCBF in prefrontal and paralimbic regions implicated in reward behavior. Thus, PYY may act centrally to modulate eating behavior via striatal networks.
Copyright © 2011. Published by Elsevier Inc.
Activation of TrkB receptors by NGFβ mimetic peptide conjugated polymersome nanoparticles.
Source
Department of Otolaryngology, Medical University of Innsbruck, Anichstr. 35, A-6020 Innsbruck, Austria; Institute of Molecular Biology, University of Innsbruck, Innsbruck, Austria.
Abstract
Activation of tyrosine kinase receptor B (TrkB), a neurotrophin receptor, has been shown to increase neuronal cell survival and promote regeneration. Stimulation of the TrkB receptor by neurotrophic growth factors has been identified as a possible therapeutic target for the treatment of neurodegenerative disorders. However, growth factor delivery is problematic due to a short half-life in-vivo. We have conjugated hNgf-EE, a short peptide mimetic of NGFβ to the surface of polymersome nanoparticles and shown that they are capable of activating the TrkB receptor in vitro in the SHSY-G7 cell line. We propose that polymersomes could act as a scaffold for the delivery of TrkB activating moieties and that the polymersome size and polyethylene glycol surface have been shown to increase in vivo retention time. These multifunctional nanoparticles have potential for the treatment of neurodegenerative disorders by TrkB activation.
Copyright © 2011. Published by Elsevier Inc.
Development of iodoacetic acid-based cysteine mass tags: Detection enhancement for cysteine-containing peptide by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
Source
SHIMADZU Corporation, Koichi Tanaka Laboratory of Advanced Science and Technology, 1 Kuwabara-cho, Nishinokyo, Nakagyo-ku, Kyoto 604-8511, Japan; SHIMADZU Corporation, Life Science Research Center, 1 Kuwabara-cho, Nishinokyo, Nakagyo-ku, Kyoto 604-8511, Japan.
Abstract
We developed and characterized 6 new cysteine mass tags for high-sensitivity peptide analysis. The structural features are: (1) iodoacetyl group for thiol tagging, (2) hydrophilic character for reducing sample loss, (3) tertiary amino, quaternary ammonium, or guanidino group for high proton affinity, and (4) no amide bonding for minimizing fragmentation of tag moiety in collision-induced dissociation. By using these tags, 2- to 200-fold MS sensitivity was achieved, compared to control peptide with carbamydomethylation.
Copyright © 2011 Elsevier Inc. All rights reserved.
Quantification of protein posttranslational modifications using stable isotope and mass spectrometry I: Principles and applications.
Source
Department of Analytical and Formulation Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
Abstract
With the increased attention to quality by design (QbD) for biopharmaceutical products, there is a demand for accurate and precise quantification methods to monitor critical quality attributes (CQAs). To address this need we have developed a mass spectrometry (MS) based method to quantify a wide range of posttranslational modifications (PTMs) in recombinant proteins using stable isotope-labeled internal standard (SILIS). The SILIS was produced through metabolic labeling where (15)N was uniformly introduced at every nitrogen atom in the studied proteins. To enhance the accuracy of the method, the levels of PTMs in SILIS were quantified using orthogonal analytical techniques. Digestion of an unknown sample mixed with SILIS generates a labeled and a nonlabeled version of each peptide. The nonlabeled and labeled counterparts coelute during RP-HPLC separation but exhibit a sufficient mass difference to be distinguished by MS detection. With the application of SILIS, numerous PTMs can be quantified in a single analysis based on the measured MS signal ratios of (15)N-labeled versus the nonlabeled pairs. Several examples using microbial and mammalian-expressed recombinant proteins demonstrated the principle and utility of this method. The results indicate that SILIS is a valuable methodology in addressing CQAs for the QbD paradigm.
Copyright © 2011 Elsevier Inc. All rights reserved.
Mechanisms by which pesticides affect insect immunity.
Source
USDA-ARS, Pollinating Insects Research Unit, Dept. Biology UMC 5310, Utah State University, Logan, UT 84322-5310, USA.
Abstract
The current state of knowledge regarding the effect of pesticides on insect immunity is reviewed here. A basic understanding of these interactions is needed for several reasons, including to improve methods for controlling pest insects in agricultural settings, for controlling insect vectors of human diseases, and for reducing mortality in beneficial insects. Bees are particularly vulnerable to sublethal pesticide exposures because they gather nectar and pollen, concentrating environmental toxins in their nests in the process. Pesticides do have effects on immunity. Organophosphates and some botanicals have been found to impact hemocyte number, differentiation, and thus affect phagocytosis. The phenoloxidase cascade and malanization have also been shown to be affected by several insecticides. Many synthetic insecticides increase oxidative stress, and this could have severe impacts on the production of some antimicrobial peptides in insects, but research is needed to determine the actual effects. Pesticides can also affect grooming behaviors, rendering insects more susceptible to disease. Despite laboratory data documenting pesticide/pathogen interactions, little field data is available at the population level.
Copyright © 2011. Published by Elsevier Inc.
The JNK inhibitor D-JNKI-1 blocks apoptotic JNK signaling in brain mitochondria.
Source
Institute for Experimental and Clinical Pharmacology, University Hospital of Schleswig-Holstein, Campus Kiel, Hospital Strasse 4, 24105 Kiel, Germany; Clinic of Nuclear Medicine, Molecular Image, Diagnostics and Therapy, University Hospital of Schleswig-Holstein, Campus Kiel, Arnold-Heller Strasse 3, House 23, 24105 Kiel, Germany.
Abstract
Kainic acid (KA) induced seizures provokes an extensive neuronal degeneration initiated by c-Jun N-terminal kinases (JNK) as central mediators of excitotoxicity. However, the actions of their individual isoforms in cellular organelles including mitochondria remain to be elucidated. Here, we have studied the activation of JNK1, JNK2 and JNK3 and their activators, mitogen-activated protein kinase kinase (MKK) 4/7, in brain mitochondria, cytosolic and nuclear fractions after KA seizures. In the mitochondrial fraction, KA significantly increased the presence of JNK1, JNK3 and MKK4 and stimulated their phosphorylation i.e. activation. The pro-apoptotic proteins, Bim and Bax were induced and, consequently, the ratio Bcl-2-Bax decreased. These changes were paralleled by the release of cytochrome c and cleavage of poly(ADP-ribose)-polymerase (PARP). The JNK peptide inhibitor, D-JNKI-1 (XG-102) reversed these pathological events in the mitochondria and almost completely abolished cytochrome c release and PARP cleavage. Importantly, JNK3, but not JNK1 or JNK2, was associated with Bim in mitochondria and D-JNKI-1 prevented the formation of this apoptotic complex. Apart from of the attenuation of c-Jun phosphorylation in the nucleus, D-JNKI-1 did not affect the level of JNK isoforms in the nuclear and cytosolic fractions. These findings provide novel insights into the mode of action of individual JNK isoforms in cell organelles and points to the JNK3 pool in mitochondria as a target of the JNK inhibitor D-JNKI-1 to confer neuroprotection.
Copyright © 2011. Published by Elsevier Inc.
A new neuronal target for beta-amyloid peptide in the rat hippocampus.
Source
Centre de Psychiatrie et Neurosciences, UMR 894, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
Abstract
In Alzheimer's disease, amyloid beta peptide (Aβ) accumulation is associated with hippocampal network dysfunction. Intrahippocampal injections of Aβ induce aberrant inhibitory septohippocampal (SH) network activity in vivo and impairment of memory processing. In the present study, we observed, after hippocampal Aβ treatment, a selective loss of neurons projecting to the medial septum (MS) and containing calbindin (CB) and/or somatostatin (SOM). Other GABAergic neuronal subpopulations were not altered. Thus, the present study identifies hippocamposeptal neuron populations as specific targets for Aβ deposits. We observed that in Aβ-treated rats but not in controls, glutamate agonist application induced rhythmic bursting in 55% of the slow-firing neurons in the medial septum. This suggests that hippocampal Aβ can trigger modifications of the septohippocampal pathway via the alteration of a specific neuronal population. Long-range hippocamposeptal GABA/calbindin neurons, targets of hippocampal amyloid deposits, are implicated in supporting network synchronization. By identifying this target, we contribute to the understanding of the mechanisms underlying deleterious effects of Aβ, one of the main agents of dementia in Alzheimer's disease.
Copyright © 2011 Elsevier Inc. All rights reserved.
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