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Last updated: 13th August 2010

Binding a heparin derived disaccharide to defensin inspired peptides: insights to antimicrobial inhibition from gas-phase measurements.
McCullough BJ, Kalapothakis JM, Chin W, Taylor K, Clarke DJ, Eastwood H, Campopiano D, Macmillan D, Dorin J, Barran PE
The School of Chemistry, The University of Edinburgh, Edinburgh, UKEH9 3JJ.
Phys Chem Chem Phys 2010 Apr;12 (14):3589-96
Due to the ubiquitous presence of polysaccharide moieties on bacterial surfaces, it is hypothesised that a peptide-saccharide interaction plays a key role during the recognition of invading microorganisms by beta-defensins. We have employed different gas-phase methods to investigate these interactions. This manuscript describes: an MS-based titration assay measuring the gas-phase binding of ten beta-defensin related peptides to a sulfated disaccharide derived from heparin (HDD); ion mobility-mass spectrometry-determined collision cross sections of 3 peptides (both free and binding HDD); and results from molecular modelling with the aim of reconciling some of our experimental observations. We observe a clear qualitative correlation between the antimicrobial activity of several beta-defensins and related peptides and their gas-phase binding to a heparin-derived disaccharide (HDD). Four of the ten peptides show >100 micromolar K(d) values with HDD, and no bacteriocidal activity, illustrating that HDD binding correlates with peptide antimicrobial activity. For five of the remaining six peptides, bacteriocidal activity was re-measured with HDD present. For the peptides containing intramolecular disulfide bonds in two out of five, bacteriocidal activity was reduced approximately 10-fold; for the remaining three peptides, which lack intramolecular disulfide bonds, HDD addition had little effect on bacteriocidal activity. The latter results are suggested to arise from the greater degree of flexibility imparted by the removal of disulfide bonds giving the peptides the ability to envelope HDD and assume a "defensin-like" fold. Thus gas-phase analysis is put forward as a powerful tool for assessing the properties of antimicrobial peptides providing valuable insights in the mechanism of antimicrobial inhibition.
Skin Inflammation Induced by the Synergistic Action of IL-17A, IL-22, Oncostatin M, IL-1{alpha}, and TNF-{alpha} Recapitulates Some Features of Psoriasis.
Guilloteau K, Paris I, Pedretti N, Boniface K, Juchaux F, Huguier V, Guillet G, Bernard FX, Lecron JC, Morel F
Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, Unités Propres de Recherche, Equipe d´Accueil, Pôle Biologie Santé, Université de Poitiers and.
Journal of immunology (Baltimore, Md. : 1950) 2010 Mar
Keratinocytes play a crucial role in the regulation of skin inflammation, responding to environmental and immune cells stimuli. They produce soluble factors that can act in an autocrine or paracrine manner on immune cells or directly on aggressors. A screening of the activities of 36 cytokines on keratinocyte gene expression identified IL-17A, IL-22, oncostatin M, TNF-alpha, and IL-1alpha as potent cytokines in inducing cutaneous inflammation. These five proinflammatory cytokines synergistically increased production of CXCL8 and beta-defensin 2 (BD2). In addition, ex vivo studies on human skin explants demonstrated upregulation of BD2, S100A7, and CXCL8 expression in response to the same combination of cytokines. In vivo intradermal injection of these five cytokines in mouse increased CXCL1, CXCL2, CXCL3, S100A9, and BD3 expression, associated with neutrophil infiltration. We confirmed and extended this synergistic effect using quantitative real-time PCR analysis and observed increased expression of nine chemokines and 12 antimicrobial peptides. Production of CXCL, CXCL5, and CXCL8 by keratinocytes stimulated in the presence of this cytokine combination was associated with increased neutrophil chemotactic activity. Similarly, high production of BD2, BD3, and S100A7 was associated with an increased antimicrobial activity. Finally, the transcriptional profile observed in this in vitro model of inflammatory keratinocytes correlated with the one of lesional psoriatic skin. Our results demonstrate the important potentiating activities of IL-17A, IL-22, oncostatin M, TNF-alpha, and IL-1alpha on keratinocytes. This is particularly interesting in the context of psoriasis where these cytokines are overexpressed and could synergize to play an important role in upregulation of chemokines and antimicrobial peptides production.
The potent adjuvant effects of chicken beta-defensin-1 when genetically fused with infectious bursal disease virus VP2 gene.
Zhang HH, Yang XM, Xie QM, Ma JY, Luo YN, Cao YC, Chen F, Bi YZ
Department of Animal Science, College of Life Sciences, Foshan University, Xian-xi Lake, Nan-hai Da-li District, Foshan 528231, Guan-dong, PR China.
Vet Immunol Immunopathol. 2010 Jul;136(1-2):92-7.
Defensins are fundamental components of innate immune response. Current data favor that defensins play vital roles on both innate and adaptive immune responses. The aim of the present study was to investigate whether the chicken beta-defensin-1 (also named avian beta-defensin-1, AvBD1) has the potent adjuvant effects on DNA vaccine encoding IBDV VP2 gene, when genetically fused with VP2 gene. The recombinant vectors pcDNA3.1(+)-VP2 and pcDNA3.1(+)-AvBD1-VP2 were constructed as the DNA vaccines. Four groups of 14-day-old chickens were intramuscularly injected with PBS buffer, empty vector pcDNA3.1(+), recombinant pcDNA3.1(+)-VP2 and pcDNA3.1(+)-AvBD1-VP2. Results showed that VP2-specific antibody levels significantly increased following two recombinant DNA vaccine administrations (p<0.05), compared with the group of PBS and empty vector. The antibody level of group immunized with pcDNA3.1(+)-AvBD1-VP2 was significantly higher than that of group immunized with pcDNA3.1(+)-VP2 after second vaccination (p<0.05). The percentages of CD3+, CD4+ and CD8+ T-cell subtypes between groups of pcDNA3.1(+)-VP2 and pcDNA3.1(+)-AvBD1-VP2 obtained significantly different (p<0.05), the latter was higher, at 7 days post-booster. The protection from IBD challenged by immunized chickens with DNA vaccines encoding IBDV VP2 gene alone was lower than that by immunized IBDV VP2 gene together with AvBD1 gene. The results indicated that AvBD1 has an adjuvant effects on improvement the IBDV VP2-DNA vaccine effectiveness.
Cellular and molecular effects of pulsed dye laser and local narrow-band UVB therapy in psoriasis.
Rácz E, de Leeuw J, Baerveldt EM, Kant M, Neumann HA, van der Fits L, Prens EP
Department of Dermatology, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.
Lasers Surg Med 2010 Mar;42 (3):201-10
BACKGROUND AND OBJECTIVES: Pulsed dye laser (PDL) therapy is effective in clearing psoriasis plaques, but the mechanism of action is only partially understood. Local narrow-band ultraviolet B (NB-UVB), which has a better-defined mode of action, is an effective standard treatment for psoriasis. Our aim was to evaluate the cellular and molecular effects of PDL and to compare them with those of local NB-UVB in order to gain further insight into their mechanisms of action in psoriasis. STUDY DESIGN/PATIENTS AND METHODS: Nineteen patients with stable plaque-type psoriasis were treated either with PDL or NB-UVB. Lesional punch biopsies were obtained from all patients before treatment. Additional biopsies were obtained at 3 and 24 hours after PDL treatment in five of these patients. In 14 patients additional biopsies were taken after 7 and 13 weeks of treatment. Samples were histopathologically examined for the level of dermal T cell infiltrate, and the expression of epidermal beta-defensin 2, immune cell-derived tumor necrosis factor (TNF)-alpha, endothelial E-selectin, vascular endothelial growth factor receptor (VEGFR) 2 and 3, and the expression of interleukin (IL)-23 before and after treatment. RESULTS: The expression of VEGFR2, VEGFR3, and E-selectin was decreased in clinically high responders within 24 hours after PDL treatment. The expression of IL-23, TNF-alpha mRNA, and E-selectin protein were significantly reduced after two PDL treatments, whereas the expression of all epidermal markers and dermal T cell infiltrates had normalized after four treatments. The expression of epidermal activation markers and E-selectin were significantly reduced after 13 weeks of NB-UVB treatment. CONCLUSIONS: The expression of epidermal activation markers and the dermal T cell infiltrates were decreased after both treatments. The decreased expression of VEGFR2 and VEGFR3 followed by the down-regulation of TNF-alpha and IL-23p19 may be contributory factors in the efficacy of PDL in stable plaque-type psoriasis. Lasers Surg. Med. 42:201-210, 2010. (c) 2010 Wiley-Liss, Inc.
Administration of vitamin d3 improves antimetastatic efficacy of cancer vaccine therapy of lewis lung carcinoma.
Zhuravel E, Efanova O, Shestakova T, Glushko N, Mezhuev O, Soldatkina M, Pogrebnoy P
Exp. Oncol. 2010 Mar;32 (1):33-9
Aim: To analyze antitumor efficacy of experimental cancer vaccine therapy combined with introduction of vitamin D3 (VD3) for treatment of Lewis lung carcinoma (3LL). Materials and Methods: Cancer vaccines composed from recombinant murine beta-defensin-2 (mBD-2) and 3LL cell lysate, or DNA, coding for mBD-2-Muc1 fusion construct cloned in pcDNA3+ vector, were prepared and used for intradermal vaccination. Experimental cancer vaccines introduced i. d. at therapeutic and prophylactic regimens to 3LLbearing C57Bl mice, were applied alone or in combination with VD3 (administered per os) and/or low-dose cyclophosphamide (CP, administered intraperitoneal). Efficacy of treatments was analyzed by primary tumor growth dynamics indexes and by metastasis rate in vaccinated animals. Results: As it has been shown, administration of the protein-based vaccine composed from mBD-2 and 3LL cell lysate in combination with VD3 and CP, but not in VD3 free setting, led to significant suppression of primary tumor growth ( p p p p p in vivo .
Novel synthetic, salt-resistant analogs of human beta-defensins 1 and 3 endowed with enhanced antimicrobial activity.
Scudiero O, Galdiero S, Cantisani M, Di Noto R, Vitiello M, Galdiero M, Naclerio G, Cassiman JJ, Pedone C, Castaldo G, Salvatore F
CEINGE-Biotecnologie Avanzate, Naples, Italy.
Antimicrob Agents Chemother. 2010 Jun;54(6):2312-22.
Human beta-defensins (hBDs) are antimicrobial peptides of human innate immunity. The antimicrobial activity of hBDs 1, 2 and 4, but not hBD3, is impaired by high salt levels. We have designed and synthesized seven novel hBD analogs, constituted by different domains of hBD1 (which is constitutively expressed in humans) and of hBD3 (which is induced by microorganisms and inflammatory factors in humans), that would maintain and potentially increase the wild-type antimicrobial activities and be salt-resistant. We have compared the antibacterial, antiviral and chemotactic activity of the analogs versus hBD1 and hBD3. We show that the hBD1 internal region and the hBD3 C-terminal region are critical for antibacterial activity also at high salt concentrations, whereas the deletion of the N-terminal region of hBD3 results in an increase of antibacterial activity. All analogs inhibited Herpes simplex virus; antiviral activity was enhanced by the hBD1 internal region and the hBD3 C-terminal region. Wild-type and analog peptides were chemotactic for granulocytes and monocytes irrespective of salt concentrations. These new peptides may have therapeutic potential.
Functional relationship between cationic amino acid transporters and beta-defensins: Implications for dry skin diseases and the dry eye.
Jäger K, Garreis F, Posa A, Dunse M, Paulsen FP
Department of Anatomy and Cell Biology, Martin Luther University of Halle-Wittenberg, Grosse Steinstrasse 52, D-06097 Halle/Saale, Germany.
Ann Anat. 2010 Apr 20;192(2):65-9.
The ocular surface, constantly exposed to environmental pathogens, is particularly vulnerable to infection. Hence an advanced immune defence system is essential to protect the eye from microbial attack. Antimicrobial peptides, such as beta-defensins, are essential components of the innate immune system and are the first line of defence against invaders of the eye. High concentrations of l-arginine and l-lysine are necessary for the expression of beta-defensins. These are supplied by epithelial cells in inflammatory processes. The limiting factor for initiation of beta-defensin production is the transport of l-arginine and l-lysine into the cell. This transport is performed to 80% by only one transporter system in the human, the y(+)-transporter. This group of proteins exclusively transports the cationic amino acids l-arginine, l-lysine and l-ornithine and is also known under the term cationic amino acid transporter proteins (CAT-proteins). Various infections associated with l-arginine deficiency (for example psoriasis, keratoconjuctivitis sicca) are also associated with an increase in beta-defensin production. For the first time, preliminary work has shown the expression of human CATs in ocular surface epithelia and tissues of the lacrimal apparatus indicating their relevance for diseases of the ocular surface. In this review, we summarize current knowledge on the human CATs that appear to be integrated in causal regulation cascades of beta-defensins, thereby offering novel concepts for therapeutic perspectives.
Expression systems of human beta-defensins: vectors, purification and biological activities.
Corrales-Garcia LL, Possani LD, Corzo G
Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, UNAM, Apartado Postal 510-3, 61500, Cuernavaca, Morelos, México.
Amino acids 2010 Mar
Human beta-defensins are 2-5 kDa, cationic, microbicidal peptides, which represent the first-line host defense against several Gram-negative and Gram-positive bacteria, fungi and viruses. They contain a conserved disulfide-bridge pattern of three pairs of intramolecular cystine bonds. The well-known public health problem related with the growing number of multiresistant bacteria has driven research to look for novel antibiotics, such beta-defensins and a feasible way to produce them. Heterologous expression of beta-defensins could be one way to generate large quantities of beta-defensins for clinical research; however, heterologous expression of beta-defensins has some biochemical problems, such toxicity toward the host cell, peptide degradation by proteolytic cell enzymes, size, folding constrains and low recombinant peptide yields. In this communication, several heterologous systems for producing human beta-defensins are reviewed.
Cyclic and acyclic defensins inhibit human immunodeficiency virus type-1 replication by different mechanisms.
Seidel A, Ye Y, de Armas LR, Soto M, Yarosh W, Marcsisin RA, Tran D, Selsted ME, Camerini D
Department of Molecular Biology and Biochemistry, School of Biological Sciences and Center for Virus Research, University of California Irvine, Irvine, California, United States of America.
PLoS ONE 2010 ;5 (3):e9737
Defensins are antimicrobial peptides expressed by plants and animals. In mammals there are three subfamilies of defensins, distinguished by structural features: alpha, beta and theta. Alpha and beta-defensins are linear peptides with broad anti-microbial activity that are expressed by many mammals including humans. In contrast, theta-defensins are cyclic anti-microbial peptides made by several non-human primates but not humans. All three defensin types have anti-HIV-1 activity, but their mechanisms of action differ. We studied the anti-HIV-1 activity of one defensin from each group, HNP-1 (alpha), HBD-2 (beta) and RTD-1 (theta). We examined how each defensin affected HIV-1 infection and demonstrated that the cyclic defensin RTD-1 inhibited HIV-1 entry, while acyclic HNP-1 and HBD-2 inhibited HIV-1 replication even when added 12 hours post-infection and blocked viral replication after HIV-1 cDNA formation. We further found that all three defensins downmodulated CXCR4. Moreover, RTD-1 inactivated X4 HIV-1, while HNP-1 and HBD-2 inactivated both X4 and R5 HIV-1. The data presented here show that acyclic and cyclic defensins block HIV-1 replication by shared and diverse mechanisms. Moreover, we found that HNP-1 and RTD-1 directly inhibited firefly luciferase enzymatic activity, which may affect the interpretation of previously published data.
Antimicrobial peptide-like genes in Nasonia vitripennis: a genomic perspective.
Tian C, Gao B, Fang Q, Ye G, Zhu S
BMC genomics 2010 Mar;11 (1):187
ABSTRACT: BACKGROUND: Antimicrobial peptides (AMPs) are an essential component of innate immunity which can rapidly respond to diverse microbial pathogens. Insects, as a rich source of AMPs, attract great attention of scientists in both understanding of the basic biology of the immune system and searching molecular templates for anti-infective drug design. Despite a large number of AMPs have been identified from different insect species, little information in terms of these peptides is available from parasitic insects. RESULTS: By using integrated computational approaches to systemically mining the Hymenopteran parasitic wasp Nasonia vitripennis genome, we establish the first AMP repertoire whose members exhibit extensive sequence and structural diversity and can be distinguished into multiple molecular types, including insect and fungal defensin-like peptides (DLPs) with the cysteine-stabilized alpha-helical and beta-sheet (CSalphabeta) fold; Pro- or Gly-rich abaecins and hymenoptaecins; horseshoe crab tachystatin-type AMPs with the inhibitor cystine knot (ICK) fold; and a linear alpha-helical peptide. Inducible expression pattern of seven N. vitripennis AMP genes were verified, and two representative peptides were synthesized and functionally identified to be antibacterial. In comparison with Apis mellifera (Hymenoptera) and several non-Hymenopteran model insects, N. vitripennis has evolved a complex antimicrobial immune system with more genes and larger protein precursors. Three classical strategies that are likely responsible for the complexity increase have been recognized: 1) Gene duplication; 2) Exon duplication; and 3) Exon-shuffling. CONCLUSION: The present study established the N. vitripennis peptidome associated with antimicrobial immunity by using a combined computational and experimental strategy. As the first AMP repertoire of a parasitic wasp, our results offer a basic platform for further studying the immunological and evolutionary significances of these newly discovered AMP-like genes in this class of insects.