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Sample records for inflammatory peptide supergene

  1. doublesex is a mimicry supergene.

    PubMed

    Kunte, K; Zhang, W; Tenger-Trolander, A; Palmer, D H; Martin, A; Reed, R D; Mullen, S P; Kronforst, M R

    2014-03-13

    One of the most striking examples of sexual dimorphism is sex-limited mimicry in butterflies, a phenomenon in which one sex--usually the female--mimics a toxic model species, whereas the other sex displays a different wing pattern. Sex-limited mimicry is phylogenetically widespread in the swallowtail butterfly genus Papilio, in which it is often associated with female mimetic polymorphism. In multiple polymorphic species, the entire wing pattern phenotype is controlled by a single Mendelian 'supergene'. Although theoretical work has explored the evolutionary dynamics of supergene mimicry, there are almost no empirical data that address the critical issue of what a mimicry supergene actually is at a functional level. Using an integrative approach combining genetic and association mapping, transcriptome and genome sequencing, and gene expression analyses, we show that a single gene, doublesex, controls supergene mimicry in Papilio polytes. This is in contrast to the long-held view that supergenes are likely to be controlled by a tightly linked cluster of loci. Analysis of gene expression and DNA sequence variation indicates that isoform expression differences contribute to the functional differences between dsx mimicry alleles, and protein sequence evolution may also have a role. Our results combine elements from different hypotheses for the identity of supergenes, showing that a single gene can switch the entire wing pattern among mimicry phenotypes but may require multiple, tightly linked mutations to do so.

  2. The role of antimicrobial peptides in chronic inflammatory skin diseases

    PubMed Central

    Majewski, Sławomir

    2016-01-01

    Antimicrobial peptides (AMPs) are effector molecules of the innate immune system of the skin. They present an activity against a broad spectrum of Gram-positive and Gram-negative bacteria as well as some fungi, parasites and enveloped viruses. Several inflammatory skin diseases including psoriasis, atopic dermatitis, acne vulgaris and rosacea are characterized by a dysregulated expression of AMPs. Antimicrobial peptides are excessively produced in lesional psoriatic scales or rosacea in contrast to the atopic skin that shows lower AMP levels when compared with psoriasis. The importance of the AMPs contribution to host immunity is indisputable as alterations in the antimicrobial peptide expression have been associated with various pathologic processes. This review discusses the biology and clinical relevance of antimicrobial peptides expressed in the skin and their role in the pathogenesis of inflammatory skin diseases. PMID:26985172

  3. Novel anti-inflammatory peptides as cosmeceutical peptides.

    PubMed

    Kang, Youn-A; Na, Jung-Im; Choi, Hye-Ryung; Choi, Jee-Woong; Kang, Hee-Young; Park, Kyoung-Chan

    2011-10-01

    Ultraviolet (UV) radiation induced inflammation plays an important role in the aging of human skin. Prostaglandin (PG) E(2) is the primary mediator of UVB induced photoinflammation. We screened an internal library for dipeptides that inhibited UVB induced PGE(2) synthesis but showed no cytotoxicity toward human keratinocytes. We identified three highly active inhibitory sequences, LE (Leu+Glu), MW (Met+Trp) and MY (Met+Tyr). To evaluate their efficacy in human skin, 24 sites of abdomen skin were irradiated with a 308 nm excimer laser (300 mJ/cm(2)), after which 2% LE, MW, MY or a control were applied to the irradiated sites for 24h. The erythema index (EI) was measured before and 24h after treatment. The results showed that LE and MW significantly decreased UVB induced erythema (p=0.041 and p=0.036, respectively), but ME did not. Overall, LE and MW are candidate cosmeceutical peptides that can protect skin from UVB induced photoinflammation.

  4. Peptide hydrogel in vitro non‐inflammatory potential

    PubMed Central

    Markey, A.; Workman, V. L.; Bruce, I. A.; Woolford, T. J.; Derby, B.; Miller, A. F.; Cartmell, S. H.

    2016-01-01

    Peptide‐based hydrogels have attracted significant interest in recent years as these soft, highly hydrated materials can be engineered to mimic the cell niche with significant potential applications in the biomedical field. Their potential use in vivo in particular is dependent on their biocompatibility, including their potential to cause an inflammatory response. In this work, we investigated in vitro the inflammatory potential of a β‐sheet forming peptide (FEFEFKFK; F: phenylalanine, E: glutamic acid; K: lysine) hydrogel by encapsulating murine monocytes within it (3D culture) and using the production of cytokines, IL‐β, IL‐6 and TNFα, as markers of inflammatory response. No statistically significant release of cytokines in our test sample (media + gel + cells) was observed after 48 or 72 h of culture showing that our hydrogels do not incite a pro‐inflammatory response in vitro. These results show the potential biocompatibility of these hydrogels and therefore their potential for in vivo use. The work also highlighted the difference in monocyte behaviour, proliferation and morphology changes when cultured in 2D vs. 3D. © 2016 The Authors Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd. PMID:27990715

  5. Supergenes and their role in evolution

    PubMed Central

    Thompson, M J; Jiggins, C D

    2014-01-01

    Adaptation is commonly a multidimensional problem, with changes in multiple traits required to match a complex environment. This is epitomized by balanced polymorphisms in which multiple phenotypes co-exist and are maintained in a population by a balance of selective forces. Consideration of such polymorphisms led to the concept of the supergene, where alternative phenotypes in a balanced polymorphism segregate as if controlled by a single genetic locus, resulting from tight genetic linkage between multiple functional loci. Recently, the molecular basis for several supergenes has been resolved. Thus, major chromosomal inversions have been shown to be associated with polymorphisms in butterflies, ants and birds, offering a mechanism for localised reduction in recombination. In several examples of plant self-incompatibility, the functional role of multiple elements within the supergene architecture has been demonstrated, conclusively showing that balanced polymorphism can be maintained at multiple coadapted and tightly linked elements. Despite recent criticism, we argue that the supergene concept remains relevant and is more testable than ever with modern molecular methods. PMID:24642887

  6. Formyl Peptide Receptors in Cellular Differentiation and Inflammatory Diseases.

    PubMed

    Lee, Ha Young; Lee, Mingyu; Bae, Yoe-Sik

    2017-06-01

    Formyl peptide receptors (FPRs) are a family of classical chemoattractant receptors. Although FPRs are mainly expressed in phagocytic innate immune cells including monocytes/macrophages and neutrophils, recent reports demonstrated that additional different cell types such as T-lymphocytes and several non-immune cells also express functional FPRs. FPRs were first reported as a specific receptor to detect bacteria-derived N-formyl peptides. However, accumulating evidence has shown that FPRs can recognize various ligands derived from pathogens, mitochondria, and host. This review summarizes studies on some interesting endogenous agonists for FPRs. Here, we discuss functional roles of FPRs and their ligands concerning the regulation of cellular differentiation focusing on myeloid lineage cells. Accumulating evidence also suggests that FPRs may contribute to the control of inflammatory diseases. Here, we briefly review the current understanding of the functional role of FPRs and their ligands in inflammatory disorders in some animal disease models. J. Cell. Biochem. 118: 1300-1307, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  7. Gastrointestinal neuroendocrine peptides/amines in inflammatory bowel disease

    PubMed Central

    El-Salhy, Magdy; Solomon, Tefera; Hausken, Trygve; Gilja, Odd Helge; Hatlebakk, Jan Gunnar

    2017-01-01

    Inflammatory bowel disease (IBD) is a chronic recurrent condition whose etiology is unknown, and it includes ulcerative colitis, Crohn’s disease, and microscopic colitis. These three diseases differ in clinical manifestations, courses, and prognoses. IBD reduces the patients’ quality of life and is an economic burden to both the patients and society. Interactions between the gastrointestinal (GI) neuroendocrine peptides/amines (NEPA) and the immune system are believed to play an important role in the pathophysiology of IBD. Moreover, the interaction between GI NEPA and intestinal microbiota appears to play also a pivotal role in the pathophysiology of IBD. This review summarizes the available data on GI NEPA in IBD, and speculates on their possible role in the pathophysiology and the potential use of this information when developing treatments. GI NEPA serotonin, the neuropeptide Y family, and substance P are proinflammatory, while the chromogranin/secretogranin family, vasoactive intestinal peptide, somatostatin, and ghrelin are anti-inflammatory. Several innate and adaptive immune cells express these NEPA and/or have receptors to them. The GI NEPA are affected in patients with IBD and in animal models of human IBD. The GI NEPA are potentially useful for the diagnosis and follow-up of the activity of IBD, and are candidate targets for treatments of this disease. PMID:28811704

  8. The potential impacts of formyl peptide receptor 1 in inflammatory diseases.

    PubMed

    Yang, Shun-Chin; Hwang, Tsong-Long

    2016-06-01

    Neutrophils play a critical role in acute and chronic inflammatory diseases. N-formyl peptides, which originate from bacterial peptides or mitochondrial proteins bind with a high binding affinity to formyl peptide receptor 1 (FPR1). N-formyl peptide-FPR1 is involved in the pathogenesis of sterile and infectious inflammatory processes and causes phagocytosis of pathogens or injured cells by neutrophils. Excessive activation of neutrophils by binding of N-formyl peptides is associated with tissue injury requiring drugs that block FPR1-dependent signaling. Here, we review the roles of FPR1 as a critical regulator of inflammatory processes and its involvement in pathological conditions.

  9. Calcitonin gene-related peptide as inflammatory mediator.

    PubMed

    Springer, Jochen; Geppetti, Pierangelo; Fischer, Axel; Groneberg, David A

    2003-01-01

    Sensory neuropeptides have been proposed to play a key role in the pathogenesis of a number of respiratory diseases such as asthma, chronic obstructive pulmonary disease or chronic cough. Next to prominent neuropeptides such as tachykinins or vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) has long been suggested to participate in airway physiology and pathophysiology. CGRP is a 37 amino-acid peptide which is expressed by nerve fibers projecting to the airways and by pulmonary neuroendocrine cells. The most prominent effects of CGRP in the airways are vasodilatation and in a few instances bronchoconstriction. A further pulmonary effect of CGRP is the induction of eosinophil migration and the stimulation of beta-integrin-mediated T cell adhesion to fibronectin at the site of inflammation. By contrast, CGRP inhibits macrophage secretion and the capacity of macrophages to activate T-cells, indicating a potential anti-inflammatory effect. Due to the complex pulmonary effects of CGRP with bronchoconstriction and vasodilatation and diverse immunomodulatory actions, potential anti-asthma drugs based on this peptide have not been established so far. However, targeting the effects of CGRP may be of value for future strategies in nerve modulation.

  10. A small peptide with therapeutic potential for inflammatory acne vulgaris.

    PubMed

    Zhang, Zhiye; Mu, Lixian; Tang, Jing; Duan, Zilei; Wang, Fengyu; Wei, Lin; Rong, Mingqiang; Lai, Ren

    2013-01-01

    A designed peptide named LZ1 with 15 amino acid residues containing strong antimicrobial activity against bacteria pathogens of acne vulgaris including Propionibacterium acnes, Staphylococcus epidermidis and S. aureus. Especially, it exerted strong anti-P. acnes ability. The minimal inhibitory concentration against three strains of P. acnes was only 0.6 µg/ml, which is 4 times lower than that of clindamycin. In experimental mice skin colonization model, LZ1 significantly reduced the number of P. acnes colonized on the ear, P. acnes-induced ear swelling, and inflammatory cell infiltration. It ameliorated inflammation induced by P. acnes by inhibiting the secretion of inflammatory factors including tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β. LZ1 showed little cytotoxicity on human keratinocyte and hemolytic activity on human blood red cells. Furthermore, LZ1 was very stable in human plasma. Combined with its potential bactericidal and anti-inflammatory properties, simple structure and high stability, LZ1 might be an ideal candidate for the treatment of acne.

  11. SOCS1 Mimetic Peptide Suppresses Chronic Intraocular Inflammatory Disease (Uveitis)

    PubMed Central

    He, Chang; Yu, Cheng-Rong; Mattapallil, Mary J.; Sun, Lin

    2016-01-01

    Uveitis is a potentially sight-threatening disease characterized by repeated cycles of remission and recurrent inflammation. The JAK/STAT pathway regulates the differentiation of pathogenic Th1 and Th17 cells that mediate uveitis. A SOCS1 mimetic peptide (SOCS1-KIR) that inhibits JAK2/STAT1 pathways has recently been shown to suppress experimental autoimmune uveitis (EAU). However, it is not clear whether SOCS1-KIR ameliorated uveitis by targeting JAK/STAT pathways of pathogenic lymphocytes or via inhibition of macrophages and antigen-presenting cells that also enter the retina during EAU. To further investigate mechanisms that mediate SOCS1-KIR effects and evaluate the efficacy of SOCS1-KIR as an investigational drug for chronic uveitis, we induced EAU in rats by adoptive transfer of uveitogenic T-cells and monitored disease progression and severity by slit-lamp microscopy, histology, and optical coherence tomography. Topical administration of SOCS1-KIR ameliorated acute and chronic posterior uveitis by inhibiting Th17 cells and the recruitment of inflammatory cells into retina while promoting expansion of IL-10-producing Tregs. We further show that SOCS1-KIR conferred protection of resident retinal cells that play critical role in vision from cytotoxic effects of inflammatory cytokines by downregulating proapoptotic genes. Thus, SOCS1-KIR suppresses uveitis and confers neuroprotective effects and might be exploited as a noninvasive treatment for chronic uveitis. PMID:27703302

  12. Reactive Oxygen Species, Apoptosis, Antimicrobial Peptides and Human Inflammatory Diseases

    PubMed Central

    Oyinloye, Babatunji Emmanuel; Adenowo, Abiola Fatimah; Kappo, Abidemi Paul

    2015-01-01

    Excessive free radical generation, especially reactive oxygen species (ROS) leading to oxidative stress in the biological system, has been implicated in the pathogenesis and pathological conditions associated with diverse human inflammatory diseases (HIDs). Although inflammation which is considered advantageous is a defensive mechanism in response to xenobiotics and foreign pathogen; as a result of cellular damage arising from oxidative stress, if uncontrolled, it may degenerate to chronic inflammation when the ROS levels exceed the antioxidant capacity. Therefore, in the normal resolution of inflammatory reactions, apoptosis is acknowledged to play a crucial role, while on the other hand, dysregulation in the induction of apoptosis by enhanced ROS production could also result in excessive apoptosis identified in the pathogenesis of HIDs. Apparently, a careful balance must be maintained in this complex environment. Antimicrobial peptides (AMPs) have been proposed in this review as an excellent candidate capable of playing prominent roles in maintaining this balance. Consequently, in novel drug design for the treatment and management of HIDs, AMPs are promising candidates owing to their size and multidimensional properties as well as their wide spectrum of activities and indications of reduced rate of resistance. PMID:25850012

  13. Anti-inflammatory effect of a retrovirus-derived immunosuppressive peptide in mouse models.

    PubMed

    Tolstrup, Martin; Johansen, Claus; Toft, Lars; Pedersen, Finn S; Funding, Anne; Bahrami, Shervin; Iversen, Lars; Østergaard, Lars; Duch, Mogens

    2013-11-18

    Short dimeric or mulitmeric peptides derived from a highly conserved stretch of amino acids from gammaretroviral envelope proteins has been found to have immunosuppressive properties in vitro. Here we test the hypothesis that such immunosuppressive peptides may serve as immunomodulatory reagents for treatment of inflammatory disorders. The anti-inflammatory effect of a synthetic retrovirus-derived immunosuppressive peptide of 17 amino acids was tested in two murine skin inflammation models, a TPA-induced acute toxic contact eczema model and an oxazolone-induced allergic contact dermatitis. Overall, mice (n = 24) treated with a topically applied cream containing the dimeric immunosuppressive peptide exhibited a reduction of 28.8% in ear thickness (range 20.1-42.5), whereas the application of a scrambled peptide dimer or a monomer of the immunosuppressive peptide remained without effect (p = 0.028). Furthermore, ear biopsies from mice treated with the dimeric immunosuppressive peptide showed a significant reduction in mRNA of the pro-inflammatory cytokines TNF-α, IL-17C, and IL-6 as well as the chemokine CXCL2 compared to mice treated with control peptides. Using two murine skin inflammation models, we show that an immunosuppressive retroviral peptide is capable of reducing inflammatory disorders. The results indicate that virus-derived immunosuppressive peptides capable of down-regulating several proinflammatory cytokines may represent a novel class of drugs for the treatment of excess inflammation.

  14. AP-1-Targeted Anti-Inflammatory Activities of the Nanostructured, Self-Assembling S5 Peptide

    PubMed Central

    Yang, Woo Seok; Son, Young-Jin; Kim, Mi-Yeon; Kim, Soochan; Kim, Jong-Hoon

    2015-01-01

    Peptide-based therapeutics have received increasing attention in medical research. However, the local delivery of such therapeutics poses unique challenges. Self-assembling peptides that use decorated nanofibers are one approach by which these therapeutics may be delivered. We previously found that the self-assembling K5 peptide affects the anti-inflammatory response. The aim of the present study was to investigate another self-assembling peptide, S5. Unlike the K5 peptide which has a positive charge, the S5 peptide has a free hydroxyl (-OH) group. We first examined whether the S5 peptide regulates the inflammatory response in primary cells and found that the S5 peptide reduced the production of prostaglandin E2 (PGE2) and tumor necrosis factor (TNF)-α in lipopolysaccharide- (LPS-) treated bone marrow-derived macrophages. Moreover, the S5 peptide significantly downregulated cyclooxygenase- (COX-) 2, TNF-α, and interleukin- (IL-) 1β expression by blocking the nuclear translocation of c-Jun. Consistent with this finding, the S5 peptide diminished the activation of inflammatory signaling enzymes related to p38. The S5 peptide also inhibited the formation of the p38/c-Jun signaling complex in RAW264.7 cells. Similarly, p38 and MKK3/6 were inhibited by the S5 peptide in LPS-activated peritoneal macrophages. Taken together, these results strongly suggest that the S5 peptide could exert anti-inflammatory effects by inhibiting the c-Jun/p38 signaling pathway. PMID:26074678

  15. Potential Use of Food Protein-Derived Peptides in the Treatment of Inflammatory Diseases.

    PubMed

    Santiago-Lopez, Lourdes; Gonzalez-Cordova, Aaron F; Hernandez-Mendoza, Adrian; Vallejo-Cordoba, Belinda

    2017-01-01

    In recent years, major developments in the field of inflammatory pathophysiology have clearly shown that arthritis, diabetes, intestinal bowel diseases, and obesity, which affect many people around the world, are essentially inflammatory in nature. Different anti-inflammatory drugs have been used to treat these conditions. Some people are able to take these drugs without difficulty, yet others experience negative side effects. Hence, the search for new, natural anti-inflammatory alternatives has rapidly increased in recent years. Evidence has shown that food protein-derived peptides may be one alternative for treating inflammatory diseases. Peptides are encrypted in food proteins, can be released under hydrolysis conditions, and do not cause adverse effects. Despite limited information on the mechanism of action of peptides, in vitro and animal model studies have demonstrated their potential anti-inflammatory activity. Several in vitro studies have demonstrated that peptides can inhibit different pathways of inflammation processes such as that of the nuclear factor kappalight- chain of activated B cells (NF-κB). They can also induce the production of nitric oxide synthase (iNOs) and c-Jun N-terminal kinases (JNK) as well as influence PepT1 and CaRS, the transporters of peptides to the gastrointestinal tract that are responsible for the absorption of dietary peptides in the intestine. However, contradictory evidence has been reported in clinical assays. Hence, in this review, we present the latest research on the anti-inflammatory activity of food protein-derived peptides and provide future perspectives on the use of peptides as potential natural sources of therapeutic treatments. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Lateritic, supergene rare earth element (REE) deposits

    USGS Publications Warehouse

    Cocker, Mark D.

    2014-01-01

    Intensive lateritic weathering of bedrock under tropical or sub-tropical climatic conditions can form a variety of secondary, supergene-type deposits. These secondary deposits may range in composition from aluminous bauxites to iron and niobium, and include rare earth elements (REE). Over 250 lateritic deposits of REE are currently known and many have been important sources of REE. In southeastern China, lateritic REE deposits, known as ion-adsorption type deposits, have been the world’s largest source of heavy REE (HREE). The lateritized upper parts of carbonatite intrusions are being investigated for REE in South America, Africa, Asia and Australia, with the Mt. Weld deposit in Australia being brought into production in late 2012. Lateritic REE deposits may be derived from a wide range of primary host rocks, but all have similar laterite and enrichment profiles, and are probably formed under similar climatic conditions. The weathering profile commonly consists of a depleted zone, an enriched zone, and a partially weathered zone which overlie the protolith. Lateritic weathering may commonly extend to depths of 30 to 60 m. REE are mobilized from the breakdown of primary REE-bearing minerals and redeposited in the enriched zone deeper in the weathering horizon as secondary minerals, as colloids, or adsorbed on other secondary minerals. Enrichment of REE may range from 3 to 10 times that of the source lithology; in some instances, enrichment may range up to 100 times.

  17. Evolution of dominance mechanisms at a butterfly mimicry supergene

    PubMed Central

    Le Poul, Yann; Whibley, Annabel; Chouteau, Mathieu; Prunier, Florence; Llaurens, Violaine; Joron, Mathieu

    2014-01-01

    Genetic dominance in polymorphic loci may respond to selection; however, the evolution of dominance in complex traits remains a puzzle. We analyse dominance at a wing-patterning supergene controlling local mimicry polymorphism in the butterfly Heliconius numata. Supergene alleles are associated with chromosomal inversion polymorphism, defining ancestral versus derived alleles. Using controlled crosses and the new procedure, Colour Pattern Modelling, allowing whole-wing pattern comparisons, we estimate dominance coefficients between alleles. Here we show strict dominance in sympatry favouring mimicry and inconsistent dominance throughout the wing between alleles from distant populations. Furthermore, dominance among derived alleles is uncoordinated across wing-pattern elements, producing mosaic heterozygous patterns determined by a hierarchy in colour expression. By contrast, heterozygotes with an ancestral allele show complete, coordinated dominance of the derived allele, independently of colours. Therefore, distinct dominance mechanisms have evolved in association with supergene inversions, in response to strong selection on mimicry polymorphism. PMID:25429605

  18. Granulysin-Derived Peptides Demonstrate Antimicrobial and Anti-Inflammatory Effects Against Propionibacterium acnes

    PubMed Central

    McInturff, Jamie E.; Wang, Shyh-Jeun; Machleidt, Thomas; Lin, T. Richard; Oren, Ami; Hertz, Cheryl J.; Krutzik, Stephan R.; Hart, Scott; Zeh, Karin; Anderson, Daniel H.; Gallo, Richard L.; Modlin, Robert L.; Kim, Jenny

    2015-01-01

    Propionibacterium acnes is a key therapeutic target in acne, yet this bacterium has become resistant to standard antibiotic agents. We investigated whether the human antimicrobial protein granulysin is a potential candidate for the treatment of acne. Granulysin and synthetic granulysin-derived peptides possessing a helix–loop–helix motif killed P. acnes in vitro. Modification of a helix–loop–helix peptide, 31–50, by substitution of a tryptophan for the valine at amino acid 44 (peptide 31–50v44w) to increase its interaction with bacterial surfaces also increased its antimicrobial activity. Moreover, when synthesized with d- rather than l-type amino acids, this peptide (d-31– 50v44w) became less susceptible to degradation by proteases and more effective in killing P. acnes. Granulysin peptides were bactericidal, demonstrating an advantage over standard bacteriostatic antibiotics in their control of P. acnes. Moreover, peptide d-31–50v44w killed P. acnes in isolated human microcomedone preparations. Importantly, peptides 31–50, 31–50v44w, and d-31–50v44w also have potential anti-inflammatory effects, as demonstrated by suppression of P. acnes-stimulated cytokine release. Taken together, these data suggest that granulysin peptides may be useful as topical therapeutic agents, providing alternatives to current acne therapies. PMID:16098035

  19. Poly(NIPAm-AMPS) nanoparticles for targeted delivery of anti-inflammatory cell penetrating peptides

    NASA Astrophysics Data System (ADS)

    Bartlett, Rush Lloyd, II

    Inflammatory diseases such as osteoarthritis and rheumatoid arthritis cause $127.8 billion in US healthcare expenditures each year and are the cause of disability for 27% of disabled persons in the United States. Current treatment options rarely halt disease progression and often result in significant unwanted and debilitating side effects. Our laboratory has previously developed a family of cell penetrating peptides (CPPs) which inhibit the activity of mitogen activated protein kinase activate protein kinase 2 (MK2). MK2 mediates the inflammatory response by activating Tristetraprline (TTP). Once activated, TTP rapidly stabilizes AU rich regions of pro-inflammatory cytokine mRNA which allows translation of pro-inflammatory cytokines to occur. Blocking MK2 with our labs CPPs yields a decrease in inflammatory activity but CPPs by are highly non specific and prone to rapid enzymatic degradation in vivo.. In order to increase the potency of MK2 inhibiting CPPs we have developed a novel nanoparticle drug carrier composed of poly(N-isopropylacrylamide-co-2-acrylamido-2-methyl-1-propanesulfonic acid). This drug carrier has been shown to have preliminary efficacy in vitro and ex vivo for suppressing pro-inflammatory cytokine production when releasing CPPs. This thesis will present progress made on three aims: Specific Aim 1) Create and validate a NIPAm based drug delivery system that mimics the binding and release previously observed between cell penetrating peptides and glycosaminoglycans. Specific Aim 2) Engineer degradability into poly(NIPAm-AMPS) nanoparticles to enable more drug to be released and qualify that system in vitro. Specific Aim 3) Validate poly(NIPAm-AMPS) nanoparticles for targeted drug delivery in an ex vivo inflammatory model. Overall we have developed a novel anionic nanoparticle system that is biocompatible and efficient at loading and releasing cell penetrating peptides to inflamed tissue. Once loaded with a CPP the nanoparticle drug complex is

  20. Kinin Peptides Enhance Inflammatory and Oxidative Responses Promoting Apoptosis in a Parkinson's Disease Cellular Model

    PubMed Central

    Kozik, Andrzej

    2016-01-01

    Kinin peptides ubiquitously occur in nervous tissue and participate in inflammatory processes associated with distinct neurological disorders. These substances have also been demonstrated to promote the oxidative stress. On the other hand, the importance of oxidative stress and inflammation has been emphasized in disorders that involve the neurodegenerative processes such as Parkinson's disease (PD). A growing number of reports have demonstrated the increased expression of kinin receptors in neurodegenerative diseases. In this study, the effect of bradykinin and des-Arg10-kallidin, two representative kinin peptides, was analyzed with respect to inflammatory response and induction of oxidative stress in a PD cellular model, obtained after stimulation of differentiated SK-N-SH cells with a neurotoxin, 1-methyl-4-phenylpyridinium. Kinin peptides caused an increased cytokine release and enhanced production of reactive oxygen species and NO by cells. These changes were accompanied by a loss of cell viability and a greater activation of caspases involved in apoptosis progression. Moreover, the neurotoxin and kinin peptides altered the dopamine receptor 2 expression. Kinin receptor expression was also changed by the neurotoxin. These results suggest a mediatory role of kinin peptides in the development of neurodegeneration and may offer new possibilities for its regulation by using specific antagonists of kinin receptors. PMID:27721576

  1. Chromosomal rearrangements maintain a polymorphic supergene controlling butterfly mimicry

    PubMed Central

    Joron, Mathieu; Frezal, Lise; Jones, Robert T.; Chamberlain, Nicola L.; Lee, Siu F.; Haag, Christoph R.; Whibley, Annabel; Becuwe, Michel; Baxter, Simon W.; Ferguson, Laura; Wilkinson, Paul A.; Salazar, Camilo; Davidson, Claire; Clark, Richard; Quail, Michael A.; Beasley, Helen; Glithero, Rebecca; Lloyd, Christine; Sims, Sarah; Jones, Matthew C.; Rogers, Jane; Jiggins, Chris D.; ffrench-Constant, Richard H.

    2013-01-01

    Supergenes are tight clusters of loci that facilitate the co-segregation of adaptive variation, providing integrated control of complex adaptive phenotypes1. Polymorphic supergenes, in which specific combinations of traits are maintained within a single population, were first described for ‘pin’ and ‘thrum’ floral types in Primula1 and Fagopyrum2, but classic examples are also found in insect mimicry3–5 and snail morphology6. Understanding the evolutionary mechanisms that generate these co-adapted gene sets, as well as the mode of limiting the production of unfit recombinant forms, remains a substantial challenge7–10. Here we show that individual wing-pattern morphs in the polymorphic mimetic butterfly Heliconius numata are associated with different genomic rearrangements at the supergene locus P. These rearrangements tighten the genetic linkage between at least two colour-pattern loci that are known to recombine in closely related species9–11, with complete suppression of recombination being observed in experimental crosses across a 400-kilobase interval containing at least 18 genes. In natural populations, notable patterns of linkage disequilibrium (LD) are observed across the entire P region. The resulting divergent haplotype clades and inversion breakpoints are found in complete association with wing-pattern morphs. Our results indicate that allelic combinations at known wing-patterning loci have become locked together in a polymorphic rearrangement at the Plocus, forming a supergene that acts as a simple switch between complex adaptive phenotypes found in sympatry. These findings highlight how genomic rearrangements can have a central role in the coexistence of adaptive phenotypes involving several genes acting in concert, by locally limiting recombination and gene flow. PMID:21841803

  2. Effect of anti-inflammatory supplementation with whey peptide and exercise therapy in patients with COPD.

    PubMed

    Sugawara, Keiyu; Takahashi, Hitomi; Kashiwagura, Takeshi; Yamada, Kohko; Yanagida, Satoko; Homma, Mitsunobu; Dairiki, Kazuo; Sasaki, Hajime; Kawagoshi, Atsuyoshi; Satake, Masahiro; Shioya, Takanobu

    2012-11-01

    One of the major pathophysiologies in advanced chronic obstructive pulmonary disease (COPD) has been attributed to systemic inflammation. Meta-analysis of the 2005 Cochrane Database concluded the effect of nutritional supplementation alone on stable COPD was insufficient to promote body weight gain or exercise capacity. The aim of this study was to investigate the effectiveness of nutritional supplementation therapy using a nutritional supplement containing whey peptide with low-intensity exercise therapy in stable elderly patients with COPD. In stable elderly COPD patients with %IBW and %FEV(1) of less than 110 and 80%, respectively, anti-inflammatory nutritional supplementation therapy was added to low-intensity exercise therapy. Thirty-six COPD patients were divided into those with and those without the ingestion of an anti-inflammatory nutritional supplement containing whey peptide, which exhibited an anti-inflammatory effect. These two groups were designated as the nutritional support and the control groups, respectively. The body composition, skeletal muscle strength, exercise tolerance, health-related QOL (HRQOL), and inflammatory cytokines were evaluated before and three months after nutritional support combined with exercise therapy in both the nutritional support group and the control group. In the nutritional support group, the body weight, %IBW, FM, energy intake, %AC, Alb, PImax, PEmax, 6MWD, WBI, emotional function, and CRQ total were significantly increased, and the levels of hsCRP, IL-6, IL-8, and TNF-α were reduced significantly, while no significant change was noted in any item of physiological evaluation or any biomarker in the control group. Concomitant use of a anti-inflammatory nutritional supplement containing whey peptide, which exhibits an anti-inflammatory effect, with exercise therapy in stable elderly COPD patients with %IBW<110% and %FEV(1)<80% may not only increase body weight but may also inhibit systemic inflammation and thus

  3. Fibronectin connecting segment-1 peptide inhibits pathogenic leukocyte trafficking and inflammatory demyelination in experimental models of chronic inflammatory demyelinating polyradiculoneuropathy.

    PubMed

    Dong, Chaoling; Greathouse, Kelsey M; Beacham, Rebecca L; Palladino, Steven P; Helton, E Scott; Ubogu, Eroboghene E

    2017-06-01

    The molecular determinants of pathogenic leukocyte migration across the blood-nerve barrier (BNB) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are unknown. Specific disease modifying therapies for CIDP are also lacking. Fibronectin connecting segment-1 (FNCS1), an alternatively spliced fibronectin variant expressed by microvascular endothelial cells at sites of inflammation in vitro and in situ, is a counterligand for leukocyte α4 integrin (also known as CD49d) implicated in pathogenic leukocyte trafficking in multiple sclerosis and inflammatory bowel disease. We sought to determine the role of FNCS1 in CIDP patient leukocyte trafficking across the BNB in vitro and in severe chronic demyelinating neuritis in vivo using a representative spontaneous murine CIDP model. Peripheral blood mononuclear leukocytes from 7 untreated CIDP patients were independently infused into a cytokine-treated, flow-dependent in vitro BNB model system. Time-lapse digital video microscopy was performed to visualize and quantify leukocyte trafficking, comparing FNCS1 peptide blockade to relevant controls. Fifty 24-week old female B7-2 deficient non-obese diabetic mice with spontaneous autoimmune peripheral polyneuropathy (SAPP) were treated daily with 2mg/kg FNCS1 peptide for 5days via intraperitoneal injection with appropriate controls. Neurobehavioral measures of disease severity, motor nerve electrophysiology assessments and histopathological quantification of inflammation and morphometric assessment of demyelination were performed to determine in vivo efficacy. The biological relevance of FNCS1 and CD49d in CIDP was evaluated by immunohistochemical detection in affected patient sural nerve biopsies. 25μM FNCS1 peptide maximally inhibited CIDP leukocyte trafficking at the human BNB in vitro. FNCS1 peptide treatment resulted in significant improvements in disease severity, motor electrophysiological parameters of demyelination and histological measures of

  4. Thioredoxin-mimetic peptides (TXM) inhibit inflammatory pathways associated with high-glucose and oxidative stress.

    PubMed

    Lejnev, Katia; Khomsky, Lena; Bokvist, Krister; Mistriel-Zerbib, Shani; Naveh, Tahel; Farb, Thomas Bradley; Alsina-Fernandez, Jorge; Atlas, Daphne

    2016-10-01

    Impaired insulin signaling and the associated insulin-resistance in liver, adipose tissue, and skeletal muscle, represents a hallmark of the pathogenesis of type 2-diabetes-mellitus. Here we show that in the liver of db/db mice, a murine model of obesity, type 2 diabetes, and dyslipidemia, the elevated activities of mitogen-activated protein kinases (MAPK; ERK1/2 and p38(MAPK)), and Akt/PKB are abolished by rosiglitazone-treatment, which normalizes blood glucose in db/db mice. This is unequivocal evidence of a functional link between the activation of the MAPK specific inflammatory-pathway and high-blood sugar. A similar reduction in ERK1/2, p38(MAPK), and Akt activities but without affecting blood-glucose was observed in the liver of db/db mice treated with a molecule that mimics the action of thioredoxin, called thioredoxin-mimetic peptide (TXM). N-Acetyl-Cys-Pro-Cys-amide (TXM-CB3) is a free radical scavenger, a reducing and denitrosylating reagent that protects the cells from early death induced by inflammatory pathways. TXM-CB3 also lowered MAPK signaling activated by the disruption of the thioredoxin-reductase-thioredoxin (Trx-TrxR) redox-system and restored Akt activity in rat hepatoma FAO cells. Similarly, two other TXM-peptides, N-Acetyl-Cys-Met-Lys-Cys-amide (TXM-CB13; DY70), and N-Acetyl-Cys-γGlu-Cys-Cys-amide (TXM-CB16; DY71), lowered insulin- and oxidative stress-induced ERK1/2 activation, and rescued HepG2 cells from cell death. The potential impact of TXM-peptides on inhibiting inflammatory pathways associated with high-glucose could be effective in reversing low-grade inflammation. TXM-peptides might also have the potential to improve insulin resistance by protecting from posttranslational modifications like nitrosylation. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. CXCL10 Controls Inflammatory Pain via Opioid Peptide-Containing Macrophages in Electroacupuncture

    PubMed Central

    Wang, Ying; Gehringer, Rebekka; Mousa, Shaaban A.; Hackel, Dagmar; Brack, Alexander; Rittner, Heike L.

    2014-01-01

    Acupuncture is widely used for pain treatment in patients with osteoarthritis or low back pain, but molecular mechanisms remain largely enigmatic. In the early phase of inflammation neutrophilic chemokines direct opioid-containing neutrophils in the inflamed tissue and stimulate opioid peptide release and antinociception. In this study the molecular pathway and neuroimmune connections in complete Freund's adjuvant (CFA)-induced hind paw inflammation and electroacupuncture for peripheral pain control were analyzed. Free moving Wistar rats with hind paw inflammation were treated twice with electroacupuncture at GB30 (Huan Tiao - gall bladder meridian) (day 0 and 1) and analyzed for mechanical and thermal nociceptive thresholds. The cytokine profiles as well as the expression of opioid peptides were quantified in the inflamed paw. Electroacupuncture elicited long-term antinociception blocked by local injection of anti-opioid peptide antibodies (beta-endorphin, met-enkephalin, dynorphin A). The treatment altered the cytokine profile towards an anti-inflammatory pattern but augmented interferon (IFN)-gamma and the chemokine CXCL10 (IP-10: interferon gamma-inducible protein) protein and mRNA expression with concomitant increased numbers of opioid peptide-containing CXCR3+ macrophages. In rats with CFA hind paw inflammation without acupuncture repeated injection of CXCL10 triggered opioid-mediated antinociception and increase opioid-containing macrophages. Conversely, neutralization of CXCL10 time-dependently decreased electroacupuncture-induced antinociception and the number of infiltrating opioid peptide-expressing CXCR3+ macrophages. In summary, we describe a novel function of the chemokine CXCL10 - as a regulator for an increase of opioid-containing macrophages and antinociceptive mediator in inflammatory pain and as a key chemokine regulated by electroacupuncture. PMID:24732949

  6. Annexin A1 mimetic peptide controls the inflammatory and fibrotic effects of silica particles in mice

    PubMed Central

    Trentin, P G; Ferreira, T P T; Arantes, A C S; Ciambarella, B T; Cordeiro, R S B; Flower, R J; Perretti, M; Martins, M A; Silva, P M R

    2015-01-01

    Background and Purpose Endogenous glucocorticoids are pro-resolving mediators, an example of which is the endogenous glucocorticoid-regulated protein annexin A1 (ANXA1). Because silicosis is an occupational lung disease characterized by unabated inflammation and fibrosis, in this study we tested the therapeutic properties of the N-terminal ANXA1-derived peptide annexin 1-(2-26) (Ac2-26) on experimental silicosis. Experimental Approach Swiss-Webster mice were administered silica particles intranasally and were subsequently treated with intranasal peptide Ac2-26 (200 μg per mouse) or dexamethasone (25 μg per mouse) for 7 days, starting 6 h post-challenge. Ac2-26 abolished the leukocyte infiltration, collagen deposition, granuloma formation and generation of pro-inflammatory cytokines evoked by silica; these variables were only partially inhibited by dexamethasone. Key Results A clear exacerbation of the silica-induced pathological changes was observed in ANXA1 knockout mice as compared with their wild-type (WT) littermate controls. Incubation of lung fibroblasts from WT mice with Ac2-26 in vitro reduced IL-13 or TGF-β-induced production of CCL2 (MCP-1) and collagen, but this peptide did not affect the production of CCL2 (MCP-1) by stimulated fibroblasts from formyl peptide receptor type 1 (FPR1) knockout mice. Ac2-26 also inhibited the production of CCL2 (MCP-1) from fibroblasts of FPR2 knockout mice. Conclusions and Implications Collectively, our findings reveal novel protective properties of the ANXA1 derived peptide Ac2-26 on the inflammatory and fibrotic responses induced by silica, and suggest that ANXA1 mimetic agents might be a promising strategy as innovative anti-fibrotic approaches for the treatment of silicosis. PMID:25659822

  7. Salivary gland derived peptides as a new class of anti-inflammatory agents: review of preclinical pharmacology of C-terminal peptides of SMR1 protein

    PubMed Central

    2010-01-01

    The limitations of steroidal and non steroidal anti-inflammatory drugs have prompted investigation into other biologically based therapeutics, and identification of immune selective anti-inflammatory agents of salivary origin. The traditional view of salivary glands as accessory digestive structures is changing as their importance as sources of systemically active immunoregulatory and anti-inflammatory factors is recognized. Salivary gland involvement in maintenance of whole body homeostasis is regulated by the nervous system and thus constitutes a "neuroendocrine axis". The potent anti-inflammatory activities, both in vivo and in vitro, of the tripeptide Phe-Glu-Gly (FEG) are reviewed. FEG is a carboxyl terminal peptide of the prohormone SMR1 identified in the rat submandibular salivary gland, The D-isomeric form (feG) mimics the activity of its L-isomer FEG. Macropharmacologically, feG attenuates the cardiovascular and inflammatory effects of endotoxemia and anaphylaxis, by inhibition of hypotension, leukocyte migration, vascular leak, and disruption of pulmonary function and intestinal motility. Mechanistically, feG affects activated inflammatory cells, especially neutrophils, by regulating integrins and inhibiting intracellular production of reactive oxygen species. Pharmacodynamically, feG is active at low doses (100 μg/kg) and has a long (9-12 hour) biological half life. As a therapeutic agent, feG shows promise in diseases characterized by over exuberant inflammatory responses such as systemic inflammatory response syndrome and other acute inflammatory diseases. Arthritis, sepsis, acute pancreatitis, asthma, acute respiratory inflammation, inflammatory bowel disease, and equine laminitis are potential targets for this promising therapeutic peptide. The term "Immune Selective Anti-Inflammatory Derivatives" (ImSAIDs) is proposed for salivary-derived peptides to distinguish this class of agents from corticosteroids and nonsteroidal anti-inflammatory drugs

  8. Geomorphic surfaces and supergene enrichment in Northern Chile.

    NASA Astrophysics Data System (ADS)

    Evenstar, Laura; Mather, Anne; Stuart, Finlay; Cooper, Frances; Sparks, Steve

    2014-05-01

    Supergene enrichment of porphyry copper deposits in the central Andes is thought to be closely correlated with periods of relatively humid climate and the formation of regionally extensive paleosurfaces (e.g. Mortimer, C. 1973) . In northern Chile, two such paleosurfaces have been proposed: the ca. 23 Ma Tarapaca paleosurface within the Coastal Cordillera, and the ca. 10 Ma Pacific paleosurface within the Longitudinal Valley. The Pacific paleosurface is regarded as a single stratigraphic horizon that formed due to either a marked increase in the aridity of the area (Galli-Oliver 1967), regional surface uplift that created a change in the locus of deposition (e.g. Mortimer and Rendic 1975), or a combination of the two. The formation of this surface has been associated with the timing of supergene enrichment throughout the northern Chile and southern Peru (Alpers and Brimhall 1988). Multispectral satellite mapping of the Pacific paleosurface in northern Chile using Landsat, Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) and Digital Elevation Model (DEM) imagery, combined with seismic data (Jordan et al. 2010) indicates that the Pacific paleosurface is not a single chronostratigraphic surface, as previously thought, but an amalgamation of surfaces that have both an erosional and depositional history. New in situ cosmogenic exposure dating of alluvial boulders on the paleosurface is combined with previous data (Dunai et al. 2005, Kober et al. 2007 and Evenstar et al., 2009) giving ages ranging from ca. 23 Ma to <1 Ma, supporting a multiphase and much more continuous history. By combining these apparent exposure ages with regional geomorphology, underlying sedimentology, and seismic sections, the geomorphic evolution of the Longitudinal Valley can be constrained. The results show a complex interplay between uplift within the Coastal Cordillera and Precordillera in the south and a distinct change in depositional pattern towards the north. The

  9. Supergene Gp-9 is associated polyandry and male reproductive success in fire ants

    USDA-ARS?s Scientific Manuscript database

    Supergenes are groups of loci inherited together to facilitate the co-segregation of adaptive variation. We demonstrate that facultative polyandry and male reproductive success have a simple genetic basis in the fire ant Solenopsis invicta and depend solely on male genotype within the Gp-9 supergene...

  10. The killing of neurons by beta-amyloid peptides, prions, and pro-inflammatory cytokines.

    PubMed

    Chiarini, Anna; Dal Pra, Ilaria; Whitfield, James F; Armato, Ubaldo

    2006-01-01

    Reportedly, beta-amyloid peptides (Abeta40 and Abeta42) induce the neurodegenerative changes of Alzheimer's disease (AD) both directly by interacting with components of the cell surface to trigger apoptogenic signaling and indirectly by activating astrocytes and microglia to produce excess amounts of inflammatory cytokines. A possible cell surface target for Abetas is the p75 neurotrophin receptor (p75(NTR)). By using SK-N-BE neuroblastoma cells without neurotrophin receptors or engineered to express the full-length p75(NTR) or various parts of it, we have proven that p75(NTR) does mediate the Abeta-induced cell killing via its intracellular death domain (DD). This signaling via the DD activates caspase-8, which then activates caspase-3 and apoptogenesis. We also found a strong cytocidal interaction of direct p75(NTR)-mediated and indirect pro-inflammatory cytokine-mediated neuronal damage induced by Abeta. In fact, pro-inflammatory cytokines such as TNF-alpha and IL-1beta from Abeta-activated microglia potentiated the neurotoxic action of Aalpha mediated by p75(NTR) signaling. The pro-inflammatory cytokines probably amplify neuronal damage and killing by causing astrocytes to flood their associated neurons with NO and its lethal oxidizing ONOO- derivative. Indeed, we have found that a combination of three major pro-inflammatory cytokines, IL-1beta+IFN-gamma+TNF-alpha, causes normal adult human astrocytes (NAHA) to express nitric oxide synthase-2 (NOS-2) and make dangerously large amounts of NO via mitogen-activated protein kinases (MAPKs). Soluble Abeta40, the major amyloid precursor protein cleavage product, by itself stimulates astrocytes to express NOS-2 and make NO, possibly by activating p75(NTR) receptors, which they share with neurons, and can considerably amplify NOS-2 expression by the pro-inflammatory cytokine trio. These observations have uncovered a deadly synergistic interaction of Abeta peptides with pro-inflammatory cytokines in the neuron

  11. Purification and function of two analgesic and anti-inflammatory peptides from coelomic fluid of the earthworm, Eisenia foetida.

    PubMed

    Li, Chunlong; Chen, Mengrou; Li, Xiaojie; Yang, Meifeng; Wang, Ying; Yang, Xinwang

    2017-03-01

    The potential application of anti-inflammatory and analgesic compounds in medication and therapeutic care have become of increasing interest. We purified and characterized two novel analgesic and anti-inflammatory peptides, VQ-5 and AQ-5, from the coelomic fluid of the earthworm (Eisenia foetida). Their primary structures were determined as VSSVQ and AMADQ, respectively. Both peptides, especially AQ-5, exhibited analgesic activity in mouse models of persistent neuropathic pain and inflammation. AQ-5 also inhibited tumor necrosis factor alpha and cyclooxygenase-2 production. The mitogen-activated protein kinase signaling pathway, which is involved in analgesic and anti-inflammatory functions, was inhibited by AQ-5. Thus, the analgesic and anti-inflammatory effects of these peptides, especially AQ-5, demonstrated their potential as candidates for the development of novel analgesic medicines. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Sequence analysis of carcinoembryonic antigen: identification of glycosylation sites and homology with the immunoglobulin supergene family.

    PubMed Central

    Paxton, R J; Mooser, G; Pande, H; Lee, T D; Shively, J E

    1987-01-01

    A direct method for the determination of N-linked glycosylation sites in highly glycosylated proteins is described. Carcinoembryonic antigen (CEA) and a nonspecific crossreacting antigen (NCA) were chemically deglycosylated, and peptide maps were prepared by reverse-phase HPLC. The peptides were sequenced on a gas-phase microsequencer, and glycosylation sites were identified as the phenylthiohydantoin derivative of N-acetylglucosaminylasparagine. The sequences were confirmed by fast atom bombardment mass spectrometry. Highly homologous, extended amino-terminal sequences were determined for CEA and two NCAs, NCA-95 and NCA-55. Cysteine-containing sequences for CEA and NCA-95 show up to 95% sequence homology, and the CEA sequences also show internal sequence homologies. A comparison of the CEA sequences with known protein sequences suggests that CEA may be a member of the immunoglobulin supergene family. The protein sequence data have been used to identify a genomic DNA clone for one of the NCA antigens [Thompson, J., Pande, H., Paxton, R. J., Shively, L., Padma, A., Simmer, R. L., Todd, C. W., Riggs, A. D. & Shively, J. E. (1987) Proc. Natl. Acad. Sci. USA, in press] and a cDNA clone for CEA [Zimmermann, W., Ortlieb, B., Friedrich, R. & von Kleist, S. (1987) Proc. Natl. Acad. Sci. USA, in press]. Images PMID:3469650

  13. Anti-infectious and anti-inflammatory effects of peptide fragments sequentially derived from the antimicrobial peptide centrocin 1 isolated from the green sea urchin, Strongylocentrotus droebachiensis.

    PubMed

    Björn, Camilla; Håkansson, Joakim; Myhrman, Emma; Sjöstrand, Veronika; Haug, Tor; Lindgren, Kerstin; Blencke, Hans-Matti; Stensvåg, Klara; Mahlapuu, Margit

    2012-12-13

    Bacterial resistance against antibiotic treatment has become a major threat to public health. Antimicrobial peptides (AMPs) have emerged as promising alternative agents for treatment of infectious diseases. This study characterizes novel synthetic peptides sequentially derived from the AMP centrocin 1, isolated from the green sea urchin, for their applicability as anti-infective agents.The microbicidal effect of centrocin 1 heavy chain (CEN1 HC-Br), its debrominated analogue (CEN1 HC), the C-terminal truncated variants of both peptides, i.e. CEN1 HC-Br (1-20) and CEN1 HC (1-20), as well as the cysteine to serine substituted equivalent CEN1 HC (Ser) was evaluated using minimal microbicidal concentration assay. The anti-inflammatory properties were assessed by measuring the inhibition of secretion of pro-inflammatory cytokines. All the peptides tested exhibited marked microbicidal and anti-inflammatory properties. No difference in efficacy was seen comparing CEN1 HC-Br and CEN1 HC, while the brominated variant had higher cytotoxicity. C-terminal truncation of both peptides reduced salt-tolerability of the microbicidal effect as well as anti-inflammatory actions. Also, serine substitution of cysteine residue decreased the microbicidal effect. Thus, from the peptide variants tested, CEN1 HC showed the best efficacy and safety profile. Further, CEN1 HC significantly reduced bacterial counts in two different animal models of infected wounds, while Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) failed to develop resistance against this peptide under continued selection pressure. In summary, CEN1 HC appears a promising new antimicrobial agent, and clinical studies are warranted to evaluate the applicability of this AMP for local treatment of infections in man.

  14. Nanoparticles of noble metals in the supergene zone

    NASA Astrophysics Data System (ADS)

    Zhmodik, S. M.; Kalinin, Yu. A.; Roslyakov, N. A.; Mironov, A. G.; Mikhlin, Yu. L.; Belyanin, D. K.; Nemirovskaya, N. A.; Spiridonov, A. M.; Nesterenko, G. V.; Airiyants, E. V.; Moroz, T. N.; Bul'bak, T. A.

    2012-04-01

    Formation of noble metal nanoparticles is related to various geological processes in the supergene zone. Dispersed mineral phases appear during weathering of rocks with active participation of microorganisms, formation of soil, in aqueous medium and atmosphere. Invisible gold and other noble metals are incorporated into oxides, hydroxides, and sulfides, as well as in dispersed organic and inorganic carbonic matter. Sulfide minerals that occur in bedrocks and ores unaltered by exogenic processes and in cementation zone are among the main concentrators of noble metal nanoparticles. The ability of gold particles to disaggregate is well-known and creates problems in technological and analytical practice. When Au and PGE nanoparticles and clusters occur, these problems are augmented because of their unusual reactions and physicochemical properties. The studied gold, magnetite, titanomagnetite and pyrite microspherules from cementation zone and clay minerals of laterites in Republic of Guinea widen the knowledge of their abundance and inferred formation conditions, in particular, in the contemporary supergene zone. Morphology and composition of micrometer-sized Au mineral spherules were studied with SEM and laser microprobe. The newly formed segregations of secondary gold on the surface of its residual grains were also an object of investigation. The character of such overgrowths is the most indicative for nanoparticles. The newly formed Au particles provide evidence for redistribution of ultradispersed gold during weathering. There are serious prerequisites to state that microorganisms substantially control unusual nano-sized microspherical morphology of gold particles in the supergene zone. This is supported by experiments indicating active absorption of gold by microorganisms and direct evidence for participation of Ralstonia metallidurans bacteria in the formation of peculiar corroded bacteriomorphic surface of gold grains. In addition, the areas enriched in carbon

  15. Anti-inflammatory peptide-functionalized hydrogels for insulin-secreting cell encapsulation.

    PubMed

    Su, Jing; Hu, Bi-Huang; Lowe, William L; Kaufman, Dixon B; Messersmith, Phillip B

    2010-01-01

    Pancreatic islet encapsulation within semi-permeable materials has been proposed for transplantation therapy of type I diabetes mellitus. Polymer hydrogel networks used for this purpose have been shown to provide protection from islet destruction by immunoreactive cells and antibodies. However, one of the fundamental deficiencies with current encapsulation methods is that the permselective barriers cannot protect islets from cytotoxic molecules of low molecular weight that are diffusible into the capsule material, which subsequently results in beta-cell destruction. Use of materials that can locally inhibit the interaction between the permeable small cytotoxic factors and islet cells may prolong the viability and function of encapsulated islet grafts. Here we report the design of anti-inflammatory hydrogels supporting islet cell survival in the presence of diffusible pro-inflammatory cytokines. We demonstrated that a poly(ethylene glycol)-containing hydrogel network, formed by native chemical ligation and presenting an inhibitory peptide for islet cell surface IL-1 receptor, was able to maintain the viability of encapsulated islet cells in the presence of a combination of cytokines including IL-1 beta, TNF-alpha, and INF-gamma. In stark contrast, cells encapsulated in unmodified hydrogels were mostly destroyed by cytokines which diffused into the capsules. At the same time, these peptide-modified hydrogels were able to efficiently protect encapsulated cells against beta-cell specific T-lymphocytes and maintain glucose-stimulated insulin release by islet cells. With further development, the approach of encapsulating cells and tissues within hydrogels presenting anti-inflammatory agents may represent a new strategy to improve cell and tissue graft function in transplantation and tissue engineering applications.

  16. Anti-Inflammatory Peptide Functionalized Hydrogels for Insulin-Secreting Cell Encapsulation

    PubMed Central

    Su, Jing; Hu, Bi-Huang; Lowe, William L.; Kaufman, Dixon B.; Messersmith, Phillip B.

    2009-01-01

    Pancreatic islet encapsulation within semi-permeable materials has been proposed for transplantation therapy of Type I diabetes mellitus. Polymer hydrogel networks used for this purpose have been shown to provide protection from islet destruction by immunoreactive cells and antibodies. However, one of the fundamental deficiencies with current encapsulation methods is that the permselective barriers cannot protect islets from cytotoxic molecules of low molecular weight that are diffusible into the capsule material, which subsequently results in β-cell destruction. Use of materials that can locally inhibit the interaction between the permeable small cytotoxic factors and islet cells may prolong the viability and function of encapsulated islet grafts. Here we report the design of anti-inflammatory hydrogels supporting islet cell survival in the presence of diffusible pro-inflammatory cytokines. We demonstrated that a poly(ethylene glycol)-containing hydrogel network, formed by native chemical ligation and presenting an inhibitory peptide for islet cell surface IL-1 receptor, was able to maintain the viability of encapsulated islet cells in the presence of a combination of cytokines including IL-1β, TNF-α, and INF-γ. In stark contrast, cells encapsulated in unmodified hydrogels were mostly destroyed by cytokines which diffused into the capsules. At the same time, these peptide-modified hydrogels were able to efficiently protect encapsulated cells against β-cell specific T-lymphocytes and maintain glucose-stimulated insulin release by islet cells. With further development, the approach of encapsulating cells and tissues within hydrogels presenting anti-inflammatory agents may represent a new strategy to improve cell and tissue graft function in transplantation and tissue engineering applications. PMID:19782393

  17. Role of microorganisms in the supergene alteration of lead minerals

    SciTech Connect

    Yalikova, N.N.; Ermilova, L.P.

    1986-09-01

    The transformation of galena and other lead-sulfur compounds in the supergene zone begins, according to classic concepts, with oxidation under aqueous-aerobic conditions and ends with the formation of the lead sulfate anglesite. This article considers the microbiological processes of lead-mineral transformation that occur to one degree or another in the oxide zone of ore deposits and the results of previous experiments in the alteration of lead minerals by microorganisms, as well as the new experimental material on the formation of lead dioxide. Thiobacillus ferrooxidans is an autotrophic organism requiring no organic substances; it obtains energy from the oxidation of the ferrous iron and sulfur in sulfide minerals under acidic conditions. Experiments are also described with sulfate-reducing bacteria. 12 references, 1 figure, 1 table.

  18. Immuno-Modulator Metallo-Peptide Reduces Inflammatory State in Obese Zucker Fa/Fa Rats

    PubMed Central

    Gómez-Solís, Antonieta; Reyes-Esparza, Jorge; García-Vázquez, Francisco; Álvarez-Ayala, Elizabeth; Rodríguez-Fragoso, Lourdes

    2014-01-01

    Metabolic syndrome is a prothrombotic and proinflammatory chronic state. In obesity, the adipose tissue secretes various adipokines that take part in a variety of physiological and pathophysiological processes, including immunity and inflammation. Previous studies using a liver damage model treated with the immune-modulator metallo-peptide (IMMP) showed lessening in the degree of inflammation. Therefore, this study was set up to evaluate the anti-inflammatory effect of IMMP in obese Zucker fa/fa rats. We used Zucker-Lepr fa/fa and Zucker-Lean in this protocol. The groups received IMMP 50 ng/kg by i.p., three times per week for 8 weeks. Blood samples were collected by cardiac puncture and the serum was preserved at -80°C until analysis; the liver was excised and preserved in formaldehyde 4%. Analyses were performed to determine cytokine, insulin, glucose, triglyceride and cholesterol levels in serum, and histological analysis was also performed. IMMP treatment of obese rats resulted in decreased levels of proinflammatory cytokines (leptin, lL-6, IL-1betha, INF-gamma) and a chemokine (MCP-1), and increased levels of anti-inflammatory adipokine (adiponectin). In addition, treatment decreased the damage and hepatic steatosis generated in the tissue of obese rats. The IMMP exerted an anti-inflammatory effect in obese rats and therefore may be an effective and safe therapeutic alternative in the treatment of metabolic syndrome. PMID:25324698

  19. Importance of asparagine on the conformational stability and chemical reactivity of selected anti-inflammatory peptides

    NASA Astrophysics Data System (ADS)

    Soriano-Correa, Catalina; Barrientos-Salcedo, Carolina; Campos-Fernández, Linda; Alvarado-Salazar, Andres; Esquivel, Rodolfo O.

    2015-08-01

    Inflammatory response events are initiated by a complex series of molecular reactions that generate chemical intermediaries. The structure and properties of peptides and proteins are determined by the charge distribution of their side chains, which play an essential role in its electronic structure and physicochemical properties, hence on its biological functionality. The aim of this study was to analyze the effect of changing one central amino acid, such as substituting asparagine for aspartic acid, from Cys-Asn-Ser in aqueous solution, by assessing the conformational stability, physicochemical properties, chemical reactivity and their relationship with anti-inflammatory activity; employing quantum-chemical descriptors at the M06-2X/6-311+G(d,p) level. Our results suggest that asparagine plays a more critical role than aspartic acid in the structural stability, physicochemical features, and chemical reactivity of these tripeptides. Substituent groups in the side chain cause significant changes on the conformational stability and chemical reactivity, and consequently on their anti-inflammatory activity.

  20. Antibacterial and anti-inflammatory activity of a temporin B peptide analogue on an in vitro model of cystic fibrosis.

    PubMed

    Bezzerri, Valentino; Avitabile, Concetta; Dechecchi, Maria Cristina; Lampronti, Ilaria; Borgatti, Monica; Montagner, Giulia; Cabrini, Giulio; Gambari, Roberto; Romanelli, Alessandra

    2014-10-01

    Natural peptides with antimicrobial properties are deeply investigated as tools to fight bacteria resistant to common antibiotics. Small peptides, as those belonging to the temporin family, are very attractive because their activity can easily be tuned after small modification to their primary sequence. Structure-activity studies previously reported by us allowed the identification of one peptide, analogue of temporin B, TB_KKG6A, showing, unlike temporin B, antimicrobial activity against both Gram-positive and Gram-negative bacteria. In this paper, we investigated the antimicrobial and anti-inflammatory activity of the peptide TB_KKG6A against Pseudomonas aeruginosa. Interestingly, we found that the peptide exhibits antimicrobial activity at low concentrations, being able to downregulate the pro-inflammatory chemokines and cytokines interleukin (IL)-8, IL-1β, IL-6 and tumor necrosis factor-α produced downstream infected human bronchial epithelial cells. Experiments were carried out also with temporin B, which was found to show pro-inflammatory activity. Details on the interaction between TB_KKG6A and the P. aeruginosa LPS were obtained by circular dichroism and fluorescence studies. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.

  1. ECL-cell histamine mobilization in conscious rats: effects of locally applied regulatory peptides, candidate neurotransmitters and inflammatory mediators.

    PubMed

    Norlén, P; Bernsand, M; Konagaya, T; Håkanson, R

    2001-12-01

    1. The ECL cells control gastric acid secretion by mobilizing histamine in response to circulating gastrin. In addition, the ECL cells are thought to operate under nervous control and to be influenced by local inflammatory processes. 2. The purpose of the present study was to monitor histamine mobilization from ECL cells in conscious rats in response to locally applied regulatory peptides, candidate neurotransmitters and inflammatory mediators. 3. Microdialysis probes were implanted in the submucosa of the acid-producing part of the rat stomach. Three days later, the agents to be tested were administered via the microdialysis probe and their effects on basal (48 h fast) and stimulated (intravenous infusion of gastrin-17, 3 nmol kg(-1) h(-1)) mobilization of ECL-cell histamine was monitored by continuous measurement of histamine in the perfusate (radioimmunoassay). 4. Locally administered gastrin-17 and sulfated cholecystokinin-8 mobilized histamine as did pituitary adenylate cyclase-activating peptide-27, vasoactive intestinal peptide, peptide YY, met-enkephalin, endothelin and noradrenaline, adrenaline and isoprenaline. 5. While gastrin, sulfated-cholecystokinin-8, met-enkephalin and isoprenaline induced a sustained elevation of the submucosal histamine concentration, endothelin, peptide YY, pituitary adenylate cyclase activating peptide, vasoactive intestinal peptide, noradrenaline and adrenaline induced a transient elevation. 6. Calcitonin gene-related peptide, galanin, somatostatin and the prostanoid misoprostol inhibited gastrin-stimulated histamine mobilization. 7. The gut hormones neurotensin and secretin and the neuropeptides gastrin-releasing peptide, neuropeptide Y and substance P failed to affect ECL-cell histamine mobilization, while motilin and neuromedin U-25 had weak stimulatory effects. Also acetylcholine, carbachol, serotonin and the amino acid neurotransmitters aspartate, gamma-aminobutyric acid, glutamate and glycine were inactive or weakly

  2. Low Mass Blood Peptides Discriminative of Inflammatory Bowel Disease (IBD) Severity: A Quantitative Proteomic Perspective.

    PubMed

    Wasinger, Valerie C; Yau, Yunki; Duo, Xizi; Zeng, Ming; Campbell, Beth; Shin, Sean; Luber, Raphael; Redmond, Diane; Leong, Rupert W L

    2016-01-01

    Breakdown of the protective gut barrier releases effector molecules and degradation products into the blood stream making serum and plasma ideal as a diagnostic medium. The enriched low mass proteome is unexplored as a source of differentiators for diagnosing and monitoring inflammatory bowel disease (IBD) activity, that is less invasive than colonoscopy. Differences in the enriched low mass plasma proteome (<25 kDa) were assessed by label-free quantitative mass-spectrometry. A panel of marker candidates were progressed to validation phase and "Tier-2" FDA-level validated quantitative assay. Proteins important in maintaining gut barrier function and homeostasis at the epithelial interface have been quantitated by multiple reaction monitoring in plasma and serum including both inflammatory; rheumatoid arthritis controls, and non-inflammatory healthy controls; ulcerative colitis (UC), and Crohn's disease (CD) patients. Detection by immunoblot confirmed presence at the protein level in plasma. Correlation analysis and receiver operator characteristics were used to report the sensitivity and specificity. Peptides differentiating controls from IBD originate from secreted phosphoprotein 24 (SPP24, p = 0.000086, 0.009); whereas those in remission and healthy can be differentiated in UC by SPP24 (p = 0.00023, 0.001), α-1-microglobulin (AMBP, p = 0.006) and CD by SPP24 (p = 0.019, 0.05). UC and CD can be differentiated by Guanylin (GUC2A, p = 0.001), and Secretogranin-1 (CHGB p = 0.035). Active and quiescent disease can also be differentiated in UC and CD by CHGB (p ≤ 0.023) SPP24 (p ≤ 0.023) and AMBP (UC p = 0.046). Five peptides discriminating IBD activity and severity had very little-to-no correlation to erythrocyte sedimentation rate, C-reactive protein, white cell or platelet counts. Three of these peptides were found to be binding partners to SPP24 protein alongside other known matrix proteins. These proteins have the potential to improve diagnosis and evaluate

  3. Low Mass Blood Peptides Discriminative of Inflammatory Bowel Disease (IBD) Severity: A Quantitative Proteomic Perspective*

    PubMed Central

    Yau, Yunki; Duo, Xizi; Zeng, Ming; Campbell, Beth; Shin, Sean; Luber, Raphael; Redmond, Diane; Leong, Rupert W. L.

    2016-01-01

    Breakdown of the protective gut barrier releases effector molecules and degradation products into the blood stream making serum and plasma ideal as a diagnostic medium. The enriched low mass proteome is unexplored as a source of differentiators for diagnosing and monitoring inflammatory bowel disease (IBD) activity, that is less invasive than colonoscopy. Differences in the enriched low mass plasma proteome (<25 kDa) were assessed by label-free quantitative mass-spectrometry. A panel of marker candidates were progressed to validation phase and “Tier-2” FDA-level validated quantitative assay. Proteins important in maintaining gut barrier function and homeostasis at the epithelial interface have been quantitated by multiple reaction monitoring in plasma and serum including both inflammatory; rheumatoid arthritis controls, and non-inflammatory healthy controls; ulcerative colitis (UC), and Crohn's disease (CD) patients. Detection by immunoblot confirmed presence at the protein level in plasma. Correlation analysis and receiver operator characteristics were used to report the sensitivity and specificity. Peptides differentiating controls from IBD originate from secreted phosphoprotein 24 (SPP24, p = 0.000086, 0.009); whereas those in remission and healthy can be differentiated in UC by SPP24 (p = 0.00023, 0.001), α-1-microglobulin (AMBP, p = 0.006) and CD by SPP24 (p = 0.019, 0.05). UC and CD can be differentiated by Guanylin (GUC2A, p = 0.001), and Secretogranin-1 (CHGB p = 0.035). Active and quiescent disease can also be differentiated in UC and CD by CHGB (p ≤ 0.023) SPP24 (p ≤ 0.023) and AMBP (UC p = 0.046). Five peptides discriminating IBD activity and severity had very little-to-no correlation to erythrocyte sedimentation rate, C-reactive protein, white cell or platelet counts. Three of these peptides were found to be binding partners to SPP24 protein alongside other known matrix proteins. These proteins have the potential to improve diagnosis and

  4. Age of Supergene oxidation and enrichment in the chilean porphyry copper province

    USGS Publications Warehouse

    Sillitoe, R.H.; McKee, E.H.

    1996-01-01

    Twenty-five samples of supergene alunite collected from deeply developed supergene profiles in porphyry copper deposits and prospects between latitudes 20?? and 27?? S in northern Chile yield K/Ar ages ranging from about 34 to 14 Ma. Therefore supergene oxidation and enrichment processes were active from the early Oligocene to the middle Miocene, a minimum of 20 m.y. Supergene activity at individual deposits lasted for at least 0.4 to 6.2 m.y. The early Oligocene supergene activity affected deposits in the Paleocene porphyry copper belt, whereas early and middle Miocene supergene processes are documented in the Early Cretaceous, Paleocene, and late Eocene to early Oligocene porphyry copper belts. Middle Miocene oxidation also affected the oldest epithermal gold-silver deposits in the Maricunga belt farther east. Supergene activity commenced no less than 11 m.y. after generation of each porphyry copper deposit because of the time required to unroof the copper-bearing parts of the system. Supergene activity throughout northern Chile ceased at -14 Ma. The geologic features of deposits and prospects and their morphotectonic positions, present latitudes, and present elevations display no obvious correlations with the supergene chronology. Exploration for major cumulative enrichment blankets should not be carried out either beneath thick sequences of piedmont gravels (?? ignimbrites) of Oligocene through middle Miocene age unless their accumulation is demonstrably late in the documented history of supergene activity, or in porphyry copper provinces, such as those of central Chile and northwestern Argentina, which formed after ??? 14 Ma. The uplift responsible for efficient cumulative copper enrichment is difficult to correlate convincingly with the brief pulses of compressive tectonism postulated for northern Chile and contiguous areas unless their effects were much more prolonged. Intensifying aridity is confirmed as the likely reason for the cessation of supergene

  5. Vasoactive intestinal peptide reduces the inflammatory profile in mice infected with Trypanosoma cruzi.

    PubMed

    Higyno, Pulchéria Maria Silva; Mendes, Priscila Fagundes; Miranda, Marina Barcelos de; Pereira, Dario Elias; Mota, Ana Paula Lucas; Nogueira, Katiane de Oliveira Pinto Coelho; Caldas, Ivo Santana; Moura, Sandra Aparecida de Lima; Menezes, Cristiane Alves da Silva

    2015-12-01

    Vasoactive intestinal peptide (VIP) has gained great prominence because of its therapeutic potential, which is ascribed to its ability to regulate innate immunity, inhibit antigen-specific Th1 cell responses, and generate T regulatory cells. Additionally, VIP may act as a natural antimicrobial peptide, killing bacteria, fungi, and infective forms of Trypanosoma brucei. Despite the possible relevance of VIP during the course of Chagas disease, studies regarding this in human and experimental Trypanosoma cruzi infections remain poorly characterized. In this work, we evaluated the effects of VIP on systemic and cardiac immune responses during experimental acute infection. C57BL/6 mice were infected with 5000 trypomastigotes of the VL-10 strain of T. cruzi and treated with intraperitoneal VIP injection every other day for one month. After 30 days, we observed no reduction in parasitemia levels. However, we observed a reduction in serum levels of IFN-gamma and IL-2 and an increase in that of IL-4. These data suggest that VIP treatment modified immune responses to favor the Th2 response, which had no impact on parasitemia levels although the serum level of IFN-gamma was reduced. However, this change in immune balance reduced heart damage, as noted by the smaller cardiac volume and the moderate inflammatory infiltrate observed in VIP-treated mice. Our results indicate that VIP treatment reduced the inflammatory response at the cardiac site of mice that were experimentally infected with T. cruzi. These data suggest a protective role for VIP in the heart of infected mice. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Pilose antler peptide protects osteoblasts from inflammatory and oxidative injury through EGF/EGFR signaling.

    PubMed

    Chunhui, Yang; Wenjun, Cai; Hui, Wen; Liquan, Sha; Changwei, Zhao; Tianzhu, Zhang; Wenhai, Zhao

    2017-02-16

    Epidermal growth factor (EGF)/EFG receptor (EGFR) signaling plays an important role in the osteoblastogenesis. The potential effects of pilose antler peptide (PAP) on osteoblast cell damages was investigated in our present study through EGF/EGFR signaling. In MC3T3-E1 osteoblastic cells, PAP treatment significantly inhibited the production of inflammatory cytokines by decreasing the levels of serum proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). PAP treatment also alleviated the oxidative responses as indicated by increased activities of catalase (SOD) and decreased levels of malondialdehyde (MDA). EGF inhibition, by siRNA knockdown, almost abolished PAP-induced osteoblast cytoprotection against inflammation and oxidant stress. Further, our results showed that PAP stimulated the nuclear erythroid factor 2-related factor 2 (Nrf2)2/heme oxygenase-1(HO-1) signaling, and inhibited the activation of uclear factor kappa B (NF-κB) pathway in MC3T3-E1 cells. On the other hand, EGF siRNA knockdown inhibited PAP-induced cytoprotection, which decreased the expression of Nrf-2, HO-1 and increased the level of p-NF-κBp65, p-IκBα in MC3T3-E1 cells. Thus, our research demonstrated that PAP protects osteoblasts from inflammatory and oxidative injury through EGF/EGFR signaling.

  7. Can C-peptide mediated anti-inflammatory effects retard the development of microvascular complications of type 1 diabetes?

    PubMed

    Luppi, Patrizia; Kallas, Åsa; Wahren, John

    2013-07-01

    Hyperglycemia is considered to be the major cause of microvascular complications of diabetes. Growing evidence highlights the importance of hyperglycemia-mediated inflammation in the initiation and progression of microvascular complications in type 1 diabetes. We hypothesize that lack of proinsulin C-peptide and lack of its anti-inflammatory properties contribute to the development of microvascular complications. Evidence gathered over the past 20 years shows that C-peptide is a biologically active peptide in its own right. It has been shown to reduce formation of reactive oxygen species and nuclear factor-κB activation induced by hyperglycemia, resulting in inhibition of cytokine, chemokine and cell adhesion molecule formation as well as reduced apoptotic activity. In addition, C-peptide stimulates and induces the expression of both Na⁺, K⁺-ATPase and endothelial nitric oxide synthase. Animal studies and small-scale clinical trials in type 1 diabetes patients suggest that C-peptide replacement combined with regular insulin therapy exerts beneficial effects on kidney and nerve dysfunction. Further clinical trials in patients with microvascular complications including measurements of inflammatory markers are warranted to explore the clinical significance of the aforementioned, previously unrecognized, C-peptide effects.

  8. Vasoactive intestinal peptide downregulates proinflammatory TLRs while upregulating anti-inflammatory TLRs in the infected cornea.

    PubMed

    Jiang, Xiaoyu; McClellan, Sharon A; Barrett, Ronald P; Zhang, Yunfan; Hazlett, Linda D

    2012-07-01

    TLRs recognize microbial pathogens and trigger an immune response, but their regulation by neuropeptides, such as vasoactive intestinal peptide (VIP), during Pseudomonas aeruginosa corneal infection remains unexplored. Therefore, C57BL/6 (B6) mice were injected i.p. with VIP, and mRNA, protein, and immunostaining assays were performed. After VIP treatment, PCR array and real-time RT-PCR demonstrated that proinflammatory TLRs (conserved helix-loop-helix ubiquitous kinase, IRAK1, TLR1, TLR4, TLR6, TLR8, TLR9, and TNFR-associated factor 6) were downregulated, whereas anti-inflammatory TLRs (single Ig IL-1-related receptor [SIGIRR] and ST2) were upregulated. ELISA showed that VIP modestly downregulated phosphorylated inhibitor of NF-κB kinase subunit α but upregulated ST2 ~2-fold. SIGIRR was also upregulated, whereas TLR4 immunostaining was reduced in cornea; all confirmed the mRNA data. To determine whether VIP effects were cAMP dependent, mice were injected with small interfering RNA for type 7 adenylate cyclase (AC7), with or without VIP treatment. After silencing AC7, changes in mRNA levels of TLR1, TNFR-associated factor 6, and ST2 were seen and unchanged with addition of VIP, indicating that their regulation was cAMP dependent. In contrast, changes were seen in mRNA levels of conserved helix-loop-helix ubiquitous kinase, IRAK1, 2, TLR4, 9 and SIGIRR following AC7 silencing alone; these were modified by VIP addition, indicating their cAMP independence. In vitro studies assessed the effects of VIP on TLR regulation in macrophages and Langerhans cells. VIP downregulated mRNA expression of proinflammatory TLRs while upregulating anti-inflammatory TLRs in both cell types. Collectively, the data provide evidence that VIP downregulates proinflammatory TLRs and upregulates anti-inflammatory TLRs and that this regulation is both cAMP dependent and independent and involves immune cell types found in the infected cornea.

  9. Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma

    PubMed Central

    Zhou, Shutang; Potts, Erin N.; Cuttitta, Frank; Foster, W. Michael; Sunday, Mary E.

    2011-01-01

    Gastrin-releasing peptide (GRP) is synthesized by pulmonary neuroendocrine cells in inflammatory lung diseases, such as bronchopulmonary dysplasia (BPD). Many BPD infants develop asthma, a serious disorder of intermittent airway obstruction. Despite extensive research, early mechanisms of asthma remain controversial. The incidence of asthma is growing, now affecting >300 million people worldwide. To test the hypothesis that GRP mediates asthma, we used two murine models: ozone exposure for air pollution-induced airway hyperreactivity (AHR), and ovalbumin (OVA)-induced allergic airway disease. BALB/c mice were given small molecule GRP blocking agent 77427, or GRP blocking antibody 2A11, before exposure to ozone or OVA challenge. In both models, GRP blockade abrogated AHR and bronchoalveolar lavage (BAL) macrophages and granulocytes, and decreased BAL cytokines implicated in asthma, including those typically derived from Th1 (e.g., IL-2, TNFα), Th2 (e.g., IL-5, IL-13), Th17 (IL-17), macrophages (e.g., MCP-1, IL-1), and neutrophils (KC = IL-8). Dexamethasone generally had smaller effects on all parameters. Macrophages, T cells, and neutrophils express GRP receptor (GRPR). GRP blockade diminished serine phosphorylation of GRPR with ozone or OVA. Thus, GRP mediates AHR and airway inflammation in mice, suggesting that GRP blockade is promising as a broad-spectrum therapeutic approach to treat and/or prevent asthma in humans. PMID:21252304

  10. Suppression of Propionibacterium acnes Infection and the Associated Inflammatory Response by the Antimicrobial Peptide P5 in Mice

    PubMed Central

    Ryu, Sunhyo; Han, Hyo Mi; Song, Peter I.

    2015-01-01

    The cutaneous inflammation associated with acne vulgaris is caused by the anaerobic bacterium Propionibacterium acnes through activation of the innate immune system in the skin. Current standard treatments for acne have limitations that include adverse effects and poor efficacy in many patients, making development of a more effective therapy highly desirable. In the present study, we demonstrate the protective effects of a novel customized α-helical cationic peptide, P5, against P. acnes-induced inflammatory responses in vitro and in vivo. Application of P5 significantly reduced expression of two inflammatory cytokines IL-8 and TNF-α in P. acnes-treated primary human keratinocytes, where P5 appeared to act in part by binding to bacterial lipoteichoic acid, thereby suppressing TLR2-to-NF-κB signaling. In addition, in a mouse model of acne vulgaris, P5 exerted both anti-inflammatory and antimicrobial effects against P. acnes, but exerted no cytotoxic effects against skin cells. These results demonstrate that P5, and perhaps other cationic antimicrobial peptides, offer the unique ability to reduce numbers P. acnes cells in the skin and to inhibit the inflammation they trigger. This suggests these peptides could potentially be used to effectively treat acne without adversely affecting the skin. PMID:26197393

  11. Nematode Peptides with Host-Directed Anti-inflammatory Activity Rescue Caenorhabditis elegans from a Burkholderia pseudomallei Infection

    PubMed Central

    Lim, Mei-Perng; Firdaus-Raih, Mohd; Nathan, Sheila

    2016-01-01

    Burkholderia pseudomallei, the causative agent of melioidosis, is among a growing number of bacterial pathogens that are increasingly antibiotic resistant. Antimicrobial peptides (AMPs) have been investigated as an alternative approach to treat microbial infections, as generally, there is a lower likelihood that a pathogen will develop resistance to AMPs. In this study, 36 candidate Caenorhabditis elegans genes that encode secreted peptides of <150 amino acids and previously shown to be overexpressed during infection by B. pseudomallei were identified from the expression profile of infected nematodes. RNA interference (RNAi)-based knockdown of 12/34 peptide-encoding genes resulted in enhanced nematode susceptibility to B. pseudomallei without affecting worm fitness. A microdilution test demonstrated that two peptides, NLP-31 and Y43C5A.3, exhibited anti-B. pseudomallei activity in a dose dependent manner on different pathogens. Time kill analysis proposed that these peptides were bacteriostatic against B. pseudomallei at concentrations up to 8× MIC90. The SYTOX green assay demonstrated that NLP-31 and Y43C5A.3 did not disrupt the B. pseudomallei membrane. Instead, gel retardation assays revealed that both peptides were able to bind to DNA and interfere with bacterial viability. In parallel, microscopic examination showed induction of cellular filamentation, a hallmark of DNA synthesis inhibition, of NLP-31 and Y43C5A.3 treated cells. In addition, the peptides also regulated the expression of inflammatory cytokines in B. pseudomallei infected macrophage cells. Collectively, these findings demonstrate the potential of NLP-31 and Y43C5A.3 as anti-B. pseudomallei peptides based on their function as immune modulators. PMID:27672387

  12. From topical antidote against skin irritants to a novel counter-irritating and anti-inflammatory peptide.

    PubMed

    Brodsky, Berta; Erlanger-Rosengarten, Avigail; Proscura, Elena; Shapira, Elena; Wormser, Uri

    2008-06-15

    The primary purpose of the present study was to investigate the mechanism of the counter-irritating activity of topical iodine against skin lesions induced by chemical and thermal stimuli. The hypothesis that iodine exerts its activity by inducing an endogenous anti-inflammatory factor was confirmed by exposing guinea pig skin to heat stimulus followed by topical iodine treatment and skin extraction. Injection of the extract into naïve guinea pigs reduced heat-induced irritation by 69%. The protective factor, identified as a new nonapeptide (histone H2A 36-44, H-Lys-Gly-Asn-Tyr-Ala-Glu-Arg-Ileu-Ala-OH), caused reduction of 40% in irritation score in heat-exposed guinea pigs. The murine analog (H-Lys-Gly-His-Tyr-Ala-Glu-Arg-Val-Gly-OH, termed IIIM1) reduced sulfur mustard (SM)-induced ear swelling at a dose-dependent bell-shape manner reaching peak activity of 1 mg/kg. Cultured keratinocytes transfected with the peptide were more resistant towards SM than the control cells. The peptide suppressed oxidative burst in activated neutrophils in a concentration-dependent manner. In addition, the peptide reduced glucose oxidase-induced skin edema in mice at a dose-dependent bell-shape manner. Apart from thermal and chemical-induced skin irritation this novel peptide might be of potential use in chronic dermal disorders such as psoriasis and pemphigus as well as non-dermal inflammatory diseases like multiple sclerosis, arthritis and colitis.

  13. From topical antidote against skin irritants to a novel counter-irritating and anti-inflammatory peptide

    SciTech Connect

    Brodsky, Berta; Erlanger-Rosengarten, Avigail; Proscura, Elena; Shapira, Elena; Wormser, Uri

    2008-06-15

    The primary purpose of the present study was to investigate the mechanism of the counter-irritating activity of topical iodine against skin lesions induced by chemical and thermal stimuli. The hypothesis that iodine exerts its activity by inducing an endogenous anti-inflammatory factor was confirmed by exposing guinea pig skin to heat stimulus followed by topical iodine treatment and skin extraction. Injection of the extract into naive guinea pigs reduced heat-induced irritation by 69%. The protective factor, identified as a new nonapeptide (histone H2A 36-44, H-Lys-Gly-Asn-Tyr-Ala-Glu-Arg-Ileu-Ala-OH), caused reduction of 40% in irritation score in heat-exposed guinea pigs. The murine analog (H-Lys-Gly-His-Tyr-Ala-Glu-Arg-Val-Gly-OH, termed IIIM1) reduced sulfur mustard (SM)-induced ear swelling at a dose-dependent bell-shape manner reaching peak activity of 1 mg/kg. Cultured keratinocytes transfected with the peptide were more resistant towards SM than the control cells. The peptide suppressed oxidative burst in activated neutrophils in a concentration-dependent manner. In addition, the peptide reduced glucose oxidase-induced skin edema in mice at a dose-dependent bell-shape manner. Apart from thermal and chemical-induced skin irritation this novel peptide might be of potential use in chronic dermal disorders such as psoriasis and pemphigus as well as non-dermal inflammatory diseases like multiple sclerosis, arthritis and colitis.

  14. Quaternary continental weathering geochronology by laser-heating 40Ar/39Ar analysis of supergene cryptomelane

    NASA Astrophysics Data System (ADS)

    Feng, Yuexing; Vasconcelos, Paulo

    2001-07-01

    Incremental laser-heating analyses of supergene cryptomelane clusters extracted from three distinct weathering profiles from the Mary Valley region, southeast Queensland, Australia, yield reproducible and well-defined plateau ages ranging from 346 ± 15 to 291 ± 14 ka (2 σ). Precipitation of supergene cryptomelane in this period implies that relative humid climate prevailed in southeast Queensland from 340 to 290 ka, a result consistent with oxygen isotope analyses of marine sediments from Ocean Drilling Program Site 820 and with regional pollen and spore records. These results, the first report on the precise 40Ar/39Ar dating of Quaternary supergene cryptomelane, indicate that 40Ar/39Ar analysis of pedogenic minerals provides a reliable geochronometer for the study of Quaternary surficial processes useful in the study of soil formation rates, continental paleoclimates, and archaeological sites devoid of datable volcanic minerals.

  15. Zincian dolomite related to supergene alteration in the Iglesias mining district (SW Sardinia)

    NASA Astrophysics Data System (ADS)

    Boni, M.; Mondillo, N.; Balassone, G.; Joachimski, M.; Colella, A.

    2013-01-01

    One of the main effects of supergene alteration of ore-bearing hydrothermal dolomite in areas surrounding secondary zinc orebodies ( Calamine-type nonsulfides) in southwestern Sardinia (Italy) is the formation of a broad halo of Zn dolomite. The characteristics of supergene Zn dolomite have been investigated using scanning electron microscopy and qualitative energy-dispersive X-ray spectroscopy, thermodifferential analysis, and stable isotope geochemistry. The supergene Zn dolomite is characterized by variable amounts of Zn, and low contents of Pb and Cd in the crystal lattice. It is generally depleted in Fe and Mn relative to precursor hydrothermal dolomite ( Dolomia Geodica), which occurs in two phases (stoichiometric dolomite followed by Fe-Mn-Zn-rich dolomite), well distinct in geochemistry. Mg-rich smithsonite is commonly associated to Zn dolomite. Characterization of Zn-bearing dolomite using differential thermal analysis shows a drop in temperature of the first endothermic reaction of dolomite decomposition with increasing Zn contents in dolomite. The supergene Zn dolomites have higher δ18O but lower δ13C values than hydrothermal dolomite. In comparison with smithsonite-hydrozincite, the supergene Zn dolomites have higher δ18O, but comparable δ13C values. Formation of Zn dolomite from meteoric waters is indicated by low δ13C values, suggesting the influence of soil-gas CO2 in near-surface environments. The replacement of the dolomite host by supergene Zn dolomite is interpreted as part of a multistep process, starting with a progressive "zincitization" of the dolomite crystals, followed by a patchy dedolomitization s.s. and potentially concluded by the complete replacement of dolomite by smithsonite.

  16. Robust Therapeutic Efficacy of Matrix Metalloproteinase-2-Cleavable Fas-1-RGD Peptide Complex in Chronic Inflammatory Arthritis

    PubMed Central

    Sa, Keum Hee; Sung, Shijin; Park, Jae Yong; Jo, Dong-Gyu; Park, Jae Hyung; Kim, In San; Kang, Young Mo

    2016-01-01

    Objective Therapeutic agents that are transformable via introducing cleavable linkage by locally enriched MMP-2 within inflamed synovium would enhance therapeutic efficacy on chronic inflammatory arthritis. Transforming growth factor-β-inducible gene-h3 (βig-h3), which consists of four fas-1 domains and an Arg-Gly-Asp (RGD) motif, intensifies inflammatory processes by facilitating adhesion and migration of fibroblast-like synoviocyte in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to investigate whether a MMP-2-cleavable peptide complex consisting of a fas-1 domain and an RGD peptide blocks the interaction between βig-h3 and resident cells and leads to the amelioration of inflammatory arthritis. Methods We designed βig-h3-derivatives, including the fourth fas-1 domain truncated for H1 and H2 sequences of mouse (MFK00) and MMP-2-cleavable peptide complex (MFK902). MMP-2 selectivity was examined by treatment with a series of proteases. MFK902 efficacy was determined by the adhesion and migration assay with NIH3T3 cells in vitro and collagen-induced arthritis (CIA) model using male DBA/1J mice in vivo. The mice were treated intraperitoneally with MFK902 at different dosages. Results MFK902 was specifically cleaved by active MMP-2 in a concentration-dependent manner, and βig-h3-mediated adhesion and migration were more effectively inhibited by MFK902, compared with RGD or MFK00 peptides. The arthritis activity of murine CIA, measured by clinical arthritis index and incidence of arthritic paws, was significantly ameliorated after treatment with all dosages of MFK902 (1, 10, and 30 mg/kg). MFK902 ameliorated histopathologic deterioration and reduced the expression of inflammatory mediators simultaneously with improvement of clinical features. In addition, a favorable safety profile of MFK902 was demonstrated in vivo. Conclusion The present study revealed that MMP-2-cleavable peptide complex based on βig-h3 structure is a potent and safe

  17. Anti-inflammatory effect of a human prothrombin fragment-2-derived peptide, NSA9, in EOC2 microglia

    SciTech Connect

    Kim, Ji Yeon; Kim, Tae Hyong; Kim, Soung Soo

    2008-04-11

    Pro-inflammatory mediators, such as nitric oxide (NO), prostaglandin E{sub 2} (PGE{sub 2}), and several cytokines (tumor necrosis factor (TNF)-{alpha}, interleukin (IL)-1{beta}, and IL-6) are responsible for central nervous system (CNS) injuries that include ischemia, Alzheimer's disease, and neural death. Inhibition of these pro-inflammatory mediators would be an effective therapy to reduce the progression of neurodegenerative diseases. In this study, we examined the anti-inflammatory effects of a human prothrombin fragment-2-derived peptide, NSA9 (NSAVQLVEN), on the production of pro-inflammatory mediators in lipopolysaccharide (LPS)-activated brain microglia. NSA9 significantly inhibited the release of NO, PGE{sub 2}, and pro-inflammatory cytokines in a dose-dependent manner. Furthermore, NSA9 reduced the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 mRNA and protein, which control the production of NO and PGE{sub 2}, respectively. Moreover, NSA9 suppressed the LPS-induced nuclear translocation and activation of nuclear factor-{kappa}B (NF-{kappa}B). These results suggest that NSA9 strongly inhibits the pro-inflammatory responses of microglia through the modulation of NF-{kappa}B activity.

  18. Histone deacetylase inhibition enhances antimicrobial peptide but not inflammatory cytokine expression upon bacterial challenge

    PubMed Central

    Fischer, Natalie; Sechet, Emmanuel; Friedman, Robin; Amiot, Aurélien; Sobhani, Iradj; Nigro, Giulia; Sansonetti, Philippe J.; Sperandio, Brice

    2016-01-01

    Antimicrobial peptides (AMP) are defense effectors of the innate immunity playing a crucial role in the intestinal homeostasis with commensals and protection against pathogens. Herein we aimed to investigate AMP gene regulation by deciphering specific characteristics allowing their enhanced expression among innate immune genes, particularly those encoding proinflammatory mediators. Our emphasis was on epigenetic regulation of the gene encoding the AMP β-defensin 2 (HBD2), taken as a model of possibly specific induction, upon challenge with a commensal bacterium, compared with the proinflammatory cytokine IL-8. Using an in vitro model of colonic epithelial cells challenged with Escherichia coli K12, we showed that inhibition of histone deacetylases (HDAC) by trichostatin A dramatically enhanced induction of HBD2 expression, without affecting expression of IL-8. This mechanism was supported by an increased phosphorylation of histone H3 on serine S10, preferentially at the HBD2 promoter. This process occurred through activation of the IκB kinase complex, which also led to activation of NF-κB. Moreover, we demonstrated that NF-κB was modified by acetylation upon HDAC inhibition, partly by the histone acetyltransferase p300, and that both NF-κB and p300 supported enhanced induction of HBD2 expression. Furthermore, we identified additional genes belonging to antimicrobial defense and epithelial restitution pathways that showed a similar pattern of epigenetic control. Finally, we confirmed our finding in human colonic primary cells using an ex vivo organoid model. This work opens the way to use epigenetic pharmacology to achieve induction of epithelial antimicrobial defenses, while limiting the deleterious risk of an inflammatory response. PMID:27162363

  19. Activity of antimicrobial peptide mimetics in the oral cavity: II. Activity against periopathogenic biofilms and anti-inflammatory activity.

    PubMed

    Hua, J; Scott, R W; Diamond, G

    2010-12-01

    Whereas periodontal disease is ultimately of bacterial etiology, from multispecies biofilms of gram-negative anaerobic microorganisms, much of the deleterious effects are caused by the resultant epithelial inflammatory response. Hence, development of a treatment that combines anti-biofilm antibiotic activity with anti-inflammatory activity would be of great utility. Antimicrobial peptides (AMPs) such as defensins are naturally occurring peptides that exhibit broad-spectrum activity as well as a variety of immunomodulatory activities. Furthermore, bacteria do not readily develop resistance to these agents. However, clinical studies have suggested that they do not represent optimal candidates for exogenous therapeutic agents. Small-molecule mimetics of these AMPs exhibit similar activities to the parent peptides, in addition to having low toxicity, high stability and low cost. To determine whether AMP mimetics have the potential for treatment of periodontal disease, we examined the activity of one mimetic, mPE, against biofilm cultures of Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis. Metabolic assays as well as culture and biomass measurement assays demonstrated that mPE exhibits potent activity against biofilm cultures of both species. Furthermore, as little as 2 μg ml(-1) mPE was sufficient to inhibit interleukin-1β-induced secretion of interleukin-8 in both gingival epithelial cells and THP-1 cells. This anti-inflammatory activity is associated with a reduction in activation of nuclear factor-κB, suggesting that mPE can act both as an anti-biofilm agent in an anaerobic environment and as an anti-inflammatory agent in infected tissues.

  20. Interdependencies among Selected Pro-Inflammatory Markers of Endothelial Dysfunction, C-Peptide, Anti-Inflammatory Interleukin-10 and Glucose Metabolism Disturbance in Obese Women.

    PubMed

    Janowska, Joanna; Chudek, Jerzy; Olszanecka-Glinianowicz, Magdalena; Semik-Grabarczyk, Elżbieta; Zahorska-Markiewicz, Barbara

    2016-01-01

    Currently increasing importance is attributed to the inflammatory process as a crucial factor responsible for the progressive damage to vascular walls and progression of atherosclerosis in obese people. We have studied the relationship between clinical and biochemical parameters and C-peptide and anti-inflammatory IL-10, as well as selected markers of inflammation and endothelial dysfunction such as: CCL2, CRP, sICAM-1, sVCAM-1 and E-selectin in obese women with various degree of glucose metabolism disturbance. The studied group consisted of 61 obese women, and 20 normal weight, healthy volunteers. Obese patients were spited in subgroups based on the degree of glucose metabolism disorder. Serum samples were analyzed using ELISA kits. Increased concentrations of sICAM-1, sVCAM-1, E-selectin, CCL2 and CRP were found in all obese groups compared to the normal weight subjects. In patients with Type 2 diabetes mellitus (T2DM) parameters characterizing the degree of obesity significantly positively correlated with levels of CRP and CCL2. Significant relationships were found between levels of glucose and sICAM-1and also E-selectin and HOMA-IR. C-peptide levels are positively associated with CCL2, E-selectin, triglycerides levels, and inversely with IL-10 levels in newly diagnosed T2DM group (p<0.05). Concentrations of IL-10 correlated negatively with E-selectin, CCL2, C-peptide levels, and HOMA-IR in T2DM group (p<0.05). Disturbed lipid and carbohydrate metabolism are manifested by enhanced inflammation and endothelial dysfunction in patients with simply obesity. These disturbances are associates with an increase of adhesion molecules. The results suggest the probable active participation of higher concentrations of C-peptide in the intensification of inflammatory and atherogenic processes in obese patients with type 2 diabetes. In patients with obesity and type 2 diabetes, altered serum concentrations of Il-10 seems to be dependent on the degree of insulin resistance and

  1. Bifidobacteria inhibit the inflammatory response induced by gliadins in intestinal epithelial cells via modifications of toxic peptide generation during digestion.

    PubMed

    Laparra, J M; Sanz, Y

    2010-03-01

    Celiac disease (CD) is a chronic enteropathy triggered by intake of gliadin, the toxic component of gluten. This study aims at evaluating the capacity of different Bifidobacterium strains to counteract the inflammatory effects of gliadin-derived peptides in intestinal epithelial (Caco-2) cells. A commercial extract of several gliadin (Gld) types (alpha, beta, gamma, [symbol: see text] ) was subjected to in vitro gastrointestinal digestion (pepsin at pH 3, pancreatin-bile at pH 6), inoculated or not with cell suspensions (10(8) colony forming units/ml) of either B. animalis IATA-A2, B. longum IATA-ES1, or B. bifidum IATA-ES2, in a bicameral system. The generated gliadin-derived peptides were identified by reverse phase-HPLC-ESI-MS/MS. Caco-2 cell cultures were exposed to the different gliadin peptide digestions (0.25 mg protein/ml), and the mRNA expression of nuclear factor kappa-B (NF-kappaB), tumor necrosis factor alpha (TNF-alpha), and chemokine CXCR3 receptor were analyzed by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in stimulated cells. The production of the pro-inflammatory markers NF-kappaB p50, TNF-alpha, and IL-1beta (interleukine 1beta) by Caco-2 cells was also determined by ELISA. The peptides from gliadin digestions inoculated with bifidobacteria did not exhibit the toxic amino acid sequences identified in those noninoculated (alpha/beta-Gld [158-164] and alpha/beta-Gld [122-141]). The RT-PCR analysis evidenced a down-regulation in mRNA expression of pro-inflammatory biomarkers. Consistent with these results the production of NF-kappaB, TNF-alpha, and IL-1beta was reduced (18.2-22.4%, 28.0-64.8%, and abolished, respectively) in cell cultures exposed to gliadin digestions inoculated with bifidobacteria. Therefore, bifidobacteria change the gliadin-derived peptide pattern and, thereby, attenuate their pro-inflammatory effects on Caco-2 cells.

  2. Protective effects of Lingguizhugan decoction on amyloid-beta peptide (25-35)-induced cell injury: Anti-inflammatory effects☆

    PubMed Central

    Xi, Feifei; Sang, Feng; Zhou, Chunxiang; Ling, Yun

    2012-01-01

    In the present study, a human neuroblastoma cell line (SH-SY5Y) and BV-2 microglia were treated with amyloid-β peptide (25–35), as a model of Alzheimer’s disease, to evaluate the protective effects of 10-3–10-8 g/mL Lingguizhugan decoction and to examine the underlying anti-inflammatory mechanism. Lingguizhugan decoction significantly enhanced the viability of SH-SY5Y cells with amyloid-β peptide-induced injury, and lowered levels of interleukin-1β, interleukin-6, tumor necrosis factor-α and nitric oxide in the culture supernatant of activated BV-2 microglia. The effects of 10-3 g/mL Lingguizhugan decoction were more significant. These results suggest that Lingguizhugan decoction can protect SH-SY5Y cells against amyloid-β peptide (25–35)-induced injury in a dose-dependent manner by inhibiting overexpression of inflammatory factors by activated microglia. PMID:25317138

  3. Analgesic effects of mambalgin peptide inhibitors of acid-sensing ion channels in inflammatory and neuropathic pain.

    PubMed

    Diochot, Sylvie; Alloui, Abdelkrim; Rodrigues, Précillia; Dauvois, Mélodie; Friend, Valérie; Aissouni, Youssef; Eschalier, Alain; Lingueglia, Eric; Baron, Anne

    2016-03-01

    Mambalgins are 57-amino acid peptides isolated from snake venom that evoke naloxone-resistant analgesia after local (intraplantar) and central (intrathecal) injections through inhibition of particular subtypes of acid-sensing ion channels (ASICs). We now show that mambalgins also have an opioid-independent effect on both thermal and mechanical inflammatory pain after systemic intravenous (i.v.) administration and are effective against neuropathic pain. By combining the use of knockdown and knockout animals, we show the critical involvement of peripheral ASIC1b-containing channels, along with a contribution of ASIC1a-containing channels, in the i.v. effects of these peptides against inflammatory pain. The potent analgesic effect on neuropathic pain involves 2 different mechanisms depending on the route of administration, a naloxone-insensitive and ASIC1a-independent effect associated with i.v. injection and an ASIC1a-dependent and partially naloxone-sensitive effect associated with intrathecal injection. These data further support the role of peripheral and central ASIC1-containing channels in pain, demonstrate their participation in neuropathic pain, and highlight differences in the repertoire of channels involved in different pain conditions. They also strengthen the therapeutic potential of mambalgin peptides that are active in a broader range of experimental pain models and through i.v. systemic delivery.

  4. Anti-inflammatory activity of a new cyclic peptide, citrusin XI, isolated from the fruits of Citrus unshiu.

    PubMed

    Noh, Hyung Jun; Hwang, Dukhyun; Lee, Eun Suk; Hyun, Jae Wook; Yi, Pyoung Ho; Kim, Geum Soog; Lee, Seung Eun; Pang, Changhyun; Park, Yong Joo; Chung, Kyu Hyuck; Kim, Gun Do; Kim, Ki Hyun

    2015-04-02

    Citrus unshiu (Rutaceae) is an easy-peeling citrus fruit, which has been used as a traditional Korean medicine for improving skin elasticity, relieving fatigue and cough, and preventing bronchitis, flu, and various cancers. However, its active components associated with anti-inflammation and underlying mechanisms remain unknown. In this study, we investigated the active constituents from the fruits of Citrus unshiu and evaluated the anti-inflammatory activity in order to support the traditional usage of Citrus unshiu. Repeated column chromatography, together with a semi-preparative HPLC purification was used to separate the bioactive constituent from the EtOAc soluble fraction of the EtOH extract of Citrus unshiu fruits. Anti-inflammatory effects of the isolated compounds on lipopolysaccharide (LPS)-induced production of pro-inflammatory mediators were examined using RAW264.7 macrophage cells. A new cyclic peptide, citrusin XI (1), was isolated and identified from the fruits of Citrus unshiu. The structure of compound 1 was elucidated by spectroscopic analysis, including 1D and 2D nuclear magnetic resonance (NMR) ((1)H, (13)C, COSY, HMQC and HMBC experiments), and high resolution (HR)-mass spectrometry, and its absolute configurations were further confirmed by the Marfey׳s method. Compound 1 decreased NO production in LPS-stimulated RAW264.7 cells in a dose-dependent manner with an IC50 value of 70μM. Compound 1 suppressed NO production by decreasing iNOS expression but COX-2 expression was slightly associated with the reduction by compound 1 in LPS-induced RAW264.7 cells. Furthermore, compound 1 inhibited NF-κB activation by blocking IκBα degradation and NF-κB phosphorylation in LPS-stimulated RAW264.7 cells. These results indicate that a new cyclic peptide, citrusin XI, from Citrus unshiu fruits has anti-inflammatory properties that inhibit the release of pro-inflammatory mediators. Compound 1 decreases NO production by decreasing iNOS expression and NF

  5. Anti-inflammatory and antinociceptive effects of cordymin, a peptide purified from the medicinal mushroom Cordyceps sinensis.

    PubMed

    Qian, Gui-min; Pan, Guo-Feng; Guo, Jian-You

    2012-01-01

    The anti-inflammatory and antinociceptive activities of cordymin, a peptide purified from the medicinal mushroom Cordyceps sinensis, were studied. The effects of cordymin on cytokine levels and total antioxidant activity were analysed. The antinociceptive effects of cordymin in vivo and in vitro were also determined. Cordymin treatment decreased the levels of tumour necrosis factor alpha, interleukin 1 beta and total antioxidant status. Cordymin inhibited the acetic acid-induced abdominal constrictions in mice in a dose-dependent manner. In the hot-plate test, results showed that cordymin significantly inhibited the reaction time to thermal stimuli at 30, 60 and 90 min. In neurolysin inhibition assay, cordymin showed strong activities against neurolysin (IC(50) = 0.1 µM). Our results show that cordymin is a potent anti-inflammatory and analgesic medicine.

  6. Trefoil peptide gene expression in gastrointestinal epithelial cells in inflammatory bowel disease.

    PubMed

    Wright, N A; Poulsom, R; Stamp, G; Van Norden, S; Sarraf, C; Elia, G; Ahnen, D; Jeffery, R; Longcroft, J; Pike, C

    1992-01-01

    Trefoil peptides are a growing group of proteins with interesting structural and functional properties. We have defined the pattern of trefoil peptide gene expression in the ulceration-associated cell lineage (UACL) and in the nearby mucosa in Crohn's disease. In the UACL, human spasmolytic polypeptide (hSP) mRNA is expressed in the acinar and proximal duct cells, while pS2 mRNA and peptide are found in the distal duct cells and in the surface cells. In adjacent mucosa, pS2 mRNA and protein are expressed by goblet cells, with the pS2 peptide concentrated in the area of the Golgi and also in the theca. Ultrastructural immunolocalisation showed the pS2 to be co-packaged in the mucous cell granules before being secreted into the intestinal lumen. In addition, pS2 peptide was demonstrated in local neuroendocrine cells and was also co-packaged with the neuroendocrine granules. The crypts associated with the UACL also showed marked neuroendocrine cell hyperplasia. We conclude that pS2 peptide is secreted locally into the viscoelastic coat covering the intestinal mucosa which surrounds Crohn's disease ulcers. In addition, it is clear that intestinal goblet cells, in addition to producing mucins, are a rich source of regulatory peptides. Moreover, pS2 is clearly co-packaged with neurosecretory granules, which are released through basal and lateral membranes so that the contained peptides can act in a paracrine manner. These findings are interpreted in terms of the epidermal growth factor/urogastrone released by the UACL, stimulating pS2 gene expression in surrounding cells.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. TRAM-Derived Decoy Peptides inhibits the inflammatory response in mouse mammary epithelial cells and a mastitis model in mice.

    PubMed

    Hu, Xiaoyu; Tian, Yuan; Wang, Tiancheng; Zhang, Wenlong; Wang, Wei; Gao, Xuejiao; Qu, Shihui; Cao, Yongguo; Zhang, Naisheng

    2015-10-05

    It has been proved that TRAM-Derived Decoy peptides have anti-inflammatory properties. In this study, we synthesized a TRAM-Derived decoy peptide (TM6), belongs to TRAM TIR domain, of which sequence is "N"-RQIKIWFQNRRMKWK, KENFLRDTWCNFQFY-"C" and evaluated the effects of TM6 on lipopolysaccharide-induced mastitis in mice. In vivo, LPS-induced mice mastitis model was established by injection of LPS through the duct of mammary gland. TM6 was injected 1h before or after LPS treatment. In vitro, primary mouse mammary epithelial cells were used to investigate the effects of TM6 on LPS-induced inflammatory responses. The results showed that TM6 inhibited LPS-induced mammary gland histopathologic changes, MPO activity, and TNF-α, IL-1β and IL-6 production in mice. In vitro, TM6 significantly inhibited LPS-induced TNF-α and IL-6 production, as well as NF-κB and MAPKs activation. In conclusion, this study demonstrated that TM6 had protective effects on LPS-mastitis and may be a promising therapeutic reagent for mastitis treatment.

  8. Antibody responses to peptides of peripheral nerve myelin proteins P0 and P2 in patients with inflammatory demyelinating neuropathy

    PubMed Central

    Inglis, H R; Csurhes, P A; McCombe, P A

    2007-01-01

    Background Antibodies with reactivity to peripheral nerve myelin have previously been found in the serum, and bound to peripheral nerves of patients with Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Aim To investigate the presence of antibodies reactive to specific peptide sequences within the myelin proteins P0 and P2 in patients with GBS, in patients with CIDP, in healthy controls and in patients with other neuropathies (ON). Methods Blood was obtained from 48 patients with GBS, 36 with CIDP, 48 with ON and 38 controls. ELISA was used to detect antibody responses to peptides of the human peripheral myelin proteins P0 and P2. Blood samples were collected from patients with GBS in early, peak and recovery stages of GBS to analyse antibody levels throughout the course of the disease. Results Significantly increased total IgG levels were found in patients with GBS compared with other groups. A higher percentage of patients with GBS at the peak of disease had antibody reactivity to P214–25 compared with patients with CIDP and control groups. In patients with GBS and CIDP, the percentages of patients with antibody reactivity to P261–70, and peptides derived from P0, were comparable to the control groups. Although some individual patients with GBS had high titres of reactivity to the peptide antigens tested, most patients with GBS and CIDP had levels of antibody similar to controls. Conclusion Our data suggest that increased IgG levels and increased antibody reactivity to P2 14–25 in patients with GBS at the peak of disease may play a contributory role in the disease process in some patients with demyelinating forms of GBS. PMID:17158557

  9. Martian supergene enrichment in Shalbatana Valley: Implications for Mars Early atmosphere

    NASA Astrophysics Data System (ADS)

    Popa, Ciprian; Carrozzo, Giacomo; DiAchille, Gaetano; Silvestro, Simone; Espostio, Francesca; Mennella, Vito

    2015-04-01

    The present work focuses on the detailed description of the first ever-identified supergene enrichment zone on Mars. The mineral paragenesis present at the site sets constrains on the characteristics of early Martian atmosphere. A chrysocolla/malachite bearing unit in the largest of Shalbatana Valley paleolacustrine sediment accumulation constitutes the proof for this process. The water permanence at the formation time is the main implication of this finding. Furthermore, the potential biogenic involvement at the mineralization stage adds scientific importance to the site. The latter implication could set the site as a high priority choice for future Martian in-situ robotic roving/sample-return missions. The relative age of the area (˜3.7 Ba) adds weight to this finding for purposes of planetary atmosphere evolution comparison. No Earth supergene deposit has survived that long, making this site extremely important to address the problem of the oxidative conditions of the primordial Earth and Mars atmospheres.

  10. Enhancement of the anti-inflammatory activity of temporin-1Tl-derived antimicrobial peptides by tryptophan, arginine and lysine substitutions.

    PubMed

    Rajasekaran, Ganesan; Kamalakannan, Radhakrishnan; Shin, Song Yub

    2015-10-01

    Temporin-1Tl (TL) is a 13-residue frog antimicrobial peptide (AMP) exhibiting potent antimicrobial and anti-inflammatory activity. To develop novel AMP with improved anti-inflammatory activity and antimicrobial selectivity, we designed and synthesized a series of TL analogs by substituting Trp, Arg and Lys at selected positions. Except for Escherichia coli and Staphylococcus epidermidis, all TL analogs exhibited retained or increased antimicrobial activity against seven bacterial strains including three methicillin-resistant Staphylococcus aureus strains compared with TL. TL-1 and TL-4 showed a little increase in antimicrobial selectivity, while TL-2 and TL-3 displayed slightly decreased antimicrobial selectivity because of their about twofold increased hemolytic activity. All TL analogs demonstrated greatly increased anti-inflammatory activity, evident by their higher inhibition of the production tumor necrosis factor-α (TNF-α) and nitric oxide and the mRNA expression of inducible nitric oxide synthase and TNF-α in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells, compared with TL. Taken together, the peptide anti-inflammatory activity is as follows: TL-2 ≈ TL-3 ≈ TL-4 > TL-1 > TL. In addition, LPS binding ability of the peptides corresponded with their anti-inflammatory activity. These results apparently suggest that the anti-inflammatory activity of TL analogs is associated with the direct binding ability between these peptides and LPS. Collectively, our designed TL analogs possess improved anti-inflammatory activity and retain antimicrobial activity without a significant increase in hemolysis. Therefore, it is evident that our TL analogs constitute promising candidates for the development of peptide therapeutics for gram-negative bacterial infection.

  11. The fire ant social chromosome supergene variant Sb shows low diversity but high divergence from SB.

    PubMed

    Pracana, Rodrigo; Priyam, Anurag; Levantis, Ilya; Nichols, Richard A; Wurm, Yannick

    2017-02-21

    Variation in social behavior is common yet little is known about the genetic architectures underpinning its evolution. A rare exception is in the fire ant Solenopsis invicta: Alternative variants of a supergene region determine whether a colony will have exactly one or up to dozens of queens. The two variants of this region are carried by a pair of "social chromosomes", SB and Sb, which resemble a pair of sex chromosomes. Recombination is suppressed between the two chromosomes in the supergene region. While the X-like SB can recombine with itself in SB/SB queens, recombination is effectively absent in the Y-like Sb because Sb/Sb queens die before reproducing. Here, we analyze whole genome sequences of eight haploid SB males and eight haploid Sb males. We find extensive SB-Sb di↵erentiation throughout the >19Mb long supergene region. We find no evidence of "evolutionary strata" with different levels of divergence comparable to those reported in several sex chromosomes. A high proportion of substitutions between the SB and Sb haplotypes are nonsynonymous, suggesting inefficacy of purifying selection in Sb sequences, similar to that for Y-linked sequences in XY systems. Finally, we show that the Sb haplotype of the supergene region has 635-fold less nucleotide diversity than the rest of the genome. We discuss how this reduction could be due to a recent selective sweep affecting Sb specifically or associated with a population bottleneck during the invasion of North America by the sampled population. This article is protected by copyright. All rights reserved.

  12. Significance of Anti-cyclic Citrullinated Peptide Autoantibodies in Immune-mediated Inflammatory Skin Disorders with and without Arthritis

    PubMed Central

    Grover, Chander; Kashyap, Bineeta; Daulatabad, Deepashree; Dhawan, Amit; Kaur, Iqbal R

    2016-01-01

    Background: Anti-cyclic citrullinated peptides (CCPs) are autoantibodies directed against citrullinated peptides. Rheumatoid factor (RF), an antibody against the Fc portion of IgG, is known to form immune complexes and contribute to the etiopathogenesis of various skin disorders. C-reactive protein (CRP), an acute-phase protein, increases following secretion of interleukin-6 from macrophages and T cells. Anti-CCP, RF, and CRP are well-established immune-markers, their diagnostic potential in immune-mediated skin disorders remains less widely studied. Aims and Objectives: To determine the correlation between anti-CCP, RF, and CRP in immune-mediated inflammatory skin diseases. Materials and Methods: About 61 clinically diagnosed cases of various immune-mediated skin diseases (psoriasis [n = 38], connective tissue diseases such as systemic lupus erythematosus and systemic sclerosis [n = 14], and immunobullous disorders including pemphigus vulgaris and pemphigus foliaceus [n = 9]) were included in the study. These patients were subclassified on the basis of presence or absence of arthritis. Arthritis was present in nine cases of psoriasis and seven connective tissue disorder patients. Detection of serum anti-CCP was done using enzyme-linked immunosorbent assay, whereas CRP and RF levels were detected using latex agglutination technique. Results: Of the 61 specimens, 14.75% had elevated serum anti-CCP levels. RF and CRP levels were elevated in 18.03% and 39.34% specimens, respectively. RF was elevated in 13.16% of inflammatory and 42.88% of connective tissue disorders, whereas anti-CCP was raised in 10.53% of inflammatory and 35.71% of connective tissue disorders. CRP positivity was highest in connective tissue disorders (50%), followed by 39.47% in inflammatory and 22.22% in immunobullous conditions. In none of the immunobullous patients, anti-CCP or RF levels were found to be elevated. Association of the presence of arthritis with elevated anti-CCP was found to be

  13. Significance of Anti-cyclic Citrullinated Peptide Autoantibodies in Immune-mediated Inflammatory Skin Disorders with and without Arthritis.

    PubMed

    Grover, Chander; Kashyap, Bineeta; Daulatabad, Deepashree; Dhawan, Amit; Kaur, Iqbal R

    2016-01-01

    Anti-cyclic citrullinated peptides (CCPs) are autoantibodies directed against citrullinated peptides. Rheumatoid factor (RF), an antibody against the Fc portion of IgG, is known to form immune complexes and contribute to the etiopathogenesis of various skin disorders. C-reactive protein (CRP), an acute-phase protein, increases following secretion of interleukin-6 from macrophages and T cells. Anti-CCP, RF, and CRP are well-established immune-markers, their diagnostic potential in immune-mediated skin disorders remains less widely studied. To determine the correlation between anti-CCP, RF, and CRP in immune-mediated inflammatory skin diseases. About 61 clinically diagnosed cases of various immune-mediated skin diseases (psoriasis [n = 38], connective tissue diseases such as systemic lupus erythematosus and systemic sclerosis [n = 14], and immunobullous disorders including pemphigus vulgaris and pemphigus foliaceus [n = 9]) were included in the study. These patients were subclassified on the basis of presence or absence of arthritis. Arthritis was present in nine cases of psoriasis and seven connective tissue disorder patients. Detection of serum anti-CCP was done using enzyme-linked immunosorbent assay, whereas CRP and RF levels were detected using latex agglutination technique. Of the 61 specimens, 14.75% had elevated serum anti-CCP levels. RF and CRP levels were elevated in 18.03% and 39.34% specimens, respectively. RF was elevated in 13.16% of inflammatory and 42.88% of connective tissue disorders, whereas anti-CCP was raised in 10.53% of inflammatory and 35.71% of connective tissue disorders. CRP positivity was highest in connective tissue disorders (50%), followed by 39.47% in inflammatory and 22.22% in immunobullous conditions. In none of the immunobullous patients, anti-CCP or RF levels were found to be elevated. Association of the presence of arthritis with elevated anti-CCP was found to be statistically significant. Although anti-CCP, RF, and CRP levels are

  14. A cecropin-like antimicrobial peptide with anti-inflammatory activity from the black fly salivary glands.

    PubMed

    Wu, Jing; Mu, Lixian; Zhuang, Li; Han, Yi; Liu, Tong; Li, Jun; Yang, Yuan; Yang, Hailong; Wei, Lin

    2015-10-24

    Several antimicrobial peptides (AMPs) belonging to the cecropin family have been identified from the salivary glands of different black fly species, however, the immunological functions for these molecules were poorly understood. A novel cecropin-like antimicrobial peptide (SibaCec) was purified using reverse phase high-performance liquid chromatography (RP-HPLC) from the salivary glands of the black fly Simulium bannaense. The amino acid sequence of SibaCec was determined by a combination method of automated Edman degradation and cDNA sequencing. The morphologic changes of Gram-negative bacteria Escherichia coli treated with SibaCec were assessed by scanning electron microscopy (SEM). Quantitative PCR (qPCR) was performed to analyze the mRNA expression of the inducible NO synthase (iNOS) and pro-inflammatory cytokines. Nitric oxide (NO) generation was examined using a Griess assay and the secretion of pro-inflammatory cytokines was determined by an enzyme-linked immunosorbent assay (ELISA). The activation of extracellular signal-regulated kinase (ERK), p38, and the nuclear translocation of nuclear factor-kappaB (NF-κB) were assessed by Western blotting analysis. Circular dichroism (CD) spectroscopy was performed to evaluate the secondary structure of SibaCec in solvent environment. Interaction of SibaCec with lipopolysaccharide (LPS) was studied using fluorescein isothiocyanate (FITC)- conjugated LPS aggregates. Neutralization of LPS by SibaCec was assayed with the chromogenic limulus amebocyte lysate (LAL) test. qPCR was also used to analyze the expression of SibaCec mRNA in the salivary glands of insects after oral infection with the bacteria E.coli. SibaCec possessed potent antimicrobial activity against Gram-negative bacteria, and showed low cytotoxicity toward mammalian cells. SEM analysis indicated that SibaCec killed bacteria through the disruption of cell membrane integrity. Furthermore, SibaCec significantly inhibited lipopolysaccharide (LPS

  15. Dose-Dependent Anti-Inflammatory and Neuroprotective Effects of an ανβ3 Integrin-Binding Peptide

    PubMed Central

    Han, Shu; Zhang, Fan; Hu, Zhiying; Sun, Yayi; Yang, Jing; Davies, Henry; Yew, David T. W.; Fang, Marong

    2013-01-01

    Previous studies have shown that prevention of leukocyte infiltration by targeting integrins involved in transendothelial migration may suppress the clinical and pathological features of neuroinflammatory disease. This study was designed to investigate the effects of C16, an ανβ3 integrin-binding peptide, in an acute experimental allergic encephalomyelitis (EAE) rat model. Multiple histological and immunohistochemical staining, electron microscopy observation, ELISA assay, Western blot, and magnetic resonance imaging (MRI) were employed to assess the degree of inflammation, axonal loss, neuronal apoptosis, white matter demyelination, and extent of gliosis in the brain and spinal cord of differently treated EAE models. The results showed that C16 treatment could inhibit extensive leukocyte and macrophage accumulation and infiltration and reduce cytokine tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) expression levels. A significantly lower clinical score at the peak time of disease was also demonstrated in the C16 treated group. Moreover, astrogliosis, demyelination, neuronal death, and axonal loss were all alleviated in C16 treated EAE animals, which may be attributed to the improvement of microenvironment. The data suggests that C16 peptide may act as a protective agent by attenuating inflammatory progression and thus affecting the expression of some proinflammatory cytokines during neuroinflammatory disease. PMID:24347822

  16. Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor

    PubMed Central

    Perretti, Mauro; Chiang, Nan; La, Mylinh; Fierro, Iolanda M.; Marullo, Stefano; Getting, Stephen J; Solito, Egle; Serhan, Charles N.

    2009-01-01

    Aspirin (ASA) and dexamethasone (DEX) are widely used anti-inflammatory agents yet their mechanism(s) for blocking polymorphonuclear neutrophil (PMN) accumulation at sites of inflammation remains unclear. Here, we report that inhibition of PMN infiltration by ASA and DEX is a property shared by aspirin-triggered lipoxins (ATL) and the glucocorticoid-induced annexin 1 (ANXA1)-derived peptides that are both generated in vivo and act at the lipoxin A4 receptor (ALXR/FPRL1) to halt PMN diapedesis. These structurally diverse ligands specifically interact directly with recombinant human ALXR demonstrated by specific radioligand binding and function as well as immunoprecipitation of PMN receptors. In addition, the combination of both ATL and ANXA1-derived peptides limited PMN infiltration and reduced production of inflammatory mediators (that is, prostaglandins and chemokines) in vivo. Together, these results indicate functional redundancies in endogenous lipid and peptide anti-inflammatory circuits that are spatially and temporally separate, where both ATL and specific ANXA1-derived peptides act in concert at ALXR to downregulate PMN recruitment to inflammatory loci. PMID:12368905

  17. C-type natriuretic peptide prevents kidney injury and attenuates oxidative and inflammatory responses in hemorrhagic shock.

    PubMed

    Chen, Gan; Song, Xiang; Yin, Yujing; Xia, Sha; Liu, Qingjun; You, Guoxing; Zhao, Lian; Zhou, Hong

    2017-02-01

    Oxidative stress induced by hemorrhagic shock (HS) initiates a systemic inflammatory response, which leads to subsequent kidney injury. This study assessed the efficacy of c-type natriuretic peptide (CNP) in attenuating kidney injury in a rat model of hemorrhagic shock and resuscitation (HS/R). Sodium pentobarbital-anesthetized adult male Wistar rats underwent HS induced by the withdrawal of blood to a mean arterial pressure of 30-35 mmHg for 50 min. Then, the animals received CNP (25 μg/kg) or vehicle (saline) intravenously, followed byresuscitation with 1.5 times the shed blood volume in the form of normal saline. Mean arterial pressure was measured throughout the experiment, and acid-base status, oxidative stress, inflammation, tissue injury and kidney function were evaluated after resuscitation. CNP infusion reduced the malondialdehyde content, lowered the myeloperoxidase activity and decreased the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in the kidney. The histologic injury score and the plasma creatinine concentration were also significantly decreased after CNP treatment compared to the vehicle group. CNP treatment ameliorates oxidative stress, the inflammatory response, and consequently acute kidney injury after HS/R. Thus, CNP may represent a promising strategy to improve resuscitation for the treatment of HS and deserves further investigation.

  18. Role of p75 Neurotrophin Receptor in the Neurotoxicity by β-amyloid Peptides and Synergistic Effect of Inflammatory Cytokines

    PubMed Central

    Perini, Giovanni; Della-Bianca, Vittorina; Politi, Valeria; Della Valle, Giuliano; Dal-Pra, Ilaria; Rossi, Filippo; Armato, Ubaldo

    2002-01-01

    The neurodegenerative changes in Alzheimer's disease (AD) are elicited by the accumulation of β-amyloid peptides (Aβ), which damage neurons either directly by interacting with components of the cell surface to trigger cell death signaling or indirectly by activating astrocytes and microglia to produce inflammatory mediators. It has been recently proposed that the p75 neurotrophin receptor (p75NTR) is responsible for neuronal damage by interacting with Aβ. By using neuroblastoma cell clones lacking the expression of all neurotrophin receptors or engineered to express full-length or various truncated forms of p75NTR, we could show that p75NTR is involved in the direct signaling of cell death by Aβ via the function of its death domain. This signaling leads to the activation of caspases-8 and -3, the production of reactive oxygen intermediates and the induction of an oxidative stress. We also found that the direct and indirect (inflammatory) mechanisms of neuronal damage by Aβ could act synergistically. In fact, TNF-α and IL-1β, cytokines produced by Aβ-activated microglia, could potentiate the neurotoxic action of Aβ mediated by p75NTR signaling. Together, our results indicate that neurons expressing p75NTR, mostly if expressing also proinflammatory cytokine receptors, might be preferential targets of the cytotoxic action of Aβ in AD. PMID:11927634

  19. Localization of antimicrobial peptides in the tunic of Ciona intestinalis (Ascidiacea, Tunicata) and their involvement in local inflammatory-like reactions

    PubMed Central

    Di Bella, M.A.; Fedders, H.; De Leo, G.; Leippe, M.

    2011-01-01

    Tunicates comprising a wide variety of different species synthesize antimicrobial peptides as important effector molecules of the innate immune system. Recently, two putative gene families coding for antimicrobial peptides were identified in the expressed sequence tag database of the tunicate Ciona intestinalis. Two synthetic peptides representing the cationic core region of one member of each of the families displayed potent antibacterial and antifungal activities. Moreover, the natural peptides were demonstrated to be synthesized and stored in distinct hemocyte types. Here, we investigated the presence of these natural peptides, namely Ci-MAM-A and Ci-PAP-A, in the tunic of C. intestinalis considering that the ascidian tunic is a body surface barrier exposed to constant microbial assault. Furthermore, as the tunic may represent a major route of entry for pathogen invasion after its damage we monitored the location of these peptides upon a local inflammatory-like reaction induced by injection of foreign cells. Using immunocytochemistry and electron microscopy both peptides were localized to the tunic and were massively present in granulocytes of inflamed tissue. Conclusively, antimicrobial peptides may constitute a chemical barrier within the tunic of urochordates. PMID:24371555

  20. Endocytic mechanism of internalization of dietary peptide lunasin into macrophages in inflammatory condition associated with cardiovascular disease.

    PubMed

    Cam, Anthony; Sivaguru, Mayandi; Gonzalez de Mejia, Elvira

    2013-01-01

    Cardiovascular disease (CVD) is the leading cause of death in the United States. Diet influences risk factors associated with CVD and atherosclerosis, a major vascular disease that arises from inflammation. Lunasin, a peptide derived from plant foods such as soybeans, contains a unique Arg-Gly-Asp cell-adhesion motif and inhibits the pathways involved in the inflammatory cascade. The objective was to determine the mechanism by which lunasin is internalized into human THP-1 macrophages, investigate the expression of endocytic membrane proteins in inflammatory conditions and to identify the pathways involved. While lipopolysaccharide (10 nM), vitronectin (130 nM) and a combination of these two molecules enhanced lunasin uptake and increased basal αVβ3 integrin expression, lunasin reduced αVβ3 expression by 25.5, 26.8 and 49.2%, respectively. The pretreatment of cells with brefeldin A (71 µM), an inhibitor of protein trafficking, inhibited lunasin internalization by up to 99.8%. Lunasin increased caveolin-1 expression by up to 204.8%, but did not modulate clathrin. The pretreatment of macrophages with nystatin (54 µM), an inhibitor of caveolae-dependent endocytosis, reduced lunasin internalization. The presence of amantadine (1 mM) and amiloride (1 mM), inhibitors of clathrin-mediated endocytosis and macropinocytosis, abolished lunasin cell entry. Lunasin elicited a transient reduction in intracellular levels of Ca²⁺ in LPS-induced macrophages. The results suggest that internalization of lunasin into macrophages is amplified in inflammatory conditions and is primarily mediated by endocytic mechanisms that involve integrin signaling, clathrin-coated structures and macropinosomes. Lunasin may be responsible for attenuation of CVD risk factors by interacting with pathways involved in endocytosis and inflammation.

  1. Antimicrobial cathelicidin peptide LL‑37 induces NET formation and suppresses the inflammatory response in a mouse septic model.

    PubMed

    Hosoda, Hiroshi; Nakamura, Kaho; Hu, Zhongshuang; Tamura, Hiroshi; Reich, Johannes; Kuwahara-Arai, Kyoko; Iba, Toshiaki; Tabe, Yoko; Nagaoaka, Isao

    2017-10-01

    LL‑37 is the only known member of the cathelicidin family of antimicrobial peptides in humans. In addition to its broad spectrum of antimicrobial activities, LL‑37 may modulate various inflammatory reactions. The authors previously revealed that LL‑37 improves the survival of a murine cecal ligation and puncture (CLP) sepsis model. In the present study, the mechanism for the protective action of LL‑37 was elucidated using the CLP model, focusing on the effect of LL‑37 on the release of neutrophil extracellular traps (NETs). The results indicated that the intravenous administration of LL‑37 suppressed the increase of damage-associated molecular patterns (DAMPs), including histone‑DNA complex and high‑mobility group protein 1, in addition to interleukin‑1β, tumor necrosis‑α and soluble triggering receptor expressed on myeloid cells (TREM)‑1 in plasma and peritoneal fluids. Notably, LL‑37 significantly suppressed the decrease of mononuclear cell number in blood, and the increase of polymorphonuclear cell (neutrophil) number in the peritoneal cavity during sepsis. Furthermore, LL‑37 reduced the bacterial burden in blood and peritoneal fluids. Notably, LL‑37 increased the level of NETs (myeloperoxidase‑DNA complex) in plasma and peritoneal fluids. In addition, it was verified that LL‑37 induces the release of NETs from neutrophils, and NETs possess the bactericidal activity. Overall, these observations suggest that LL‑37 improves the survival of CLP septic mice by possibly suppressing the inflammatory responses as evidenced by the inhibition of the increase of cytokines, soluble TREM‑1 and DAMPs (host cell death) and the alteration of inflammatory cell numbers, and bacterial growth via the release of NETs with bactericidal activity.

  2. Age-related effect of peptide YY (PYY) on paw edema in the rat: the function of Y1 receptors on inflammatory cells.

    PubMed

    Stanojević, Stanislava; Vujić, Vesna; Kovacević-Jovanović, Vesna; Mitić, Katarina; Kosec, Dusko; Hörsten, Stephan von; Dimitrijević, Mirjana

    2006-08-01

    It is well documented that neuropeptides participate in local inflammatory reaction and modulate functions of inflammatory cells. The aim of the study was to determine a link between in vivo and in vitro effects of NPY-related peptides on inflammatory response with respect to ageing. Peptide YY (PYY) intraplantarly applied decreases concanavalin A-induced paw edema in 3 and 8 months, but not in 24 months old male rats of Albino Oxford strain. The use of NPY-related receptor-specific peptides and Y1 receptor antagonist revealed that anti-inflammatory effect of PYY is mediated via NPY Y1 receptors. PYY in vitro decreases adherence of macrophages from 8 months, but not from 3 and 24 months old rats and this effect is also mediated via NPY Y1 receptor. Additionally, PYY (10(-6)M) decreases NBT reduction in macrophages from 3 and 8 months old rats, and suppresses NO production in cells from 24 months old rats, albeit regardless of absence of in vivo effect of PYY on inflammation in aged rats. It is concluded that aged rats are less responsive to anti-inflammatory action of PYY compared to adult and young rats, and that ageing is associated with altered NPY Y1 receptor functioning.

  3. The Anti-inflammatory Effect of the CXCR4 Antagonist-N15P Peptide and Its Modulation on Inflammation-Associated Mediators in LPS-Induced PBMC.

    PubMed

    Mo, Xue-mei; Sun, Han-xiao

    2015-01-01

    Inflammation was the important pathological process of many disease developments, but current therapeutic means for inflammatory diseases are not satisfactory. Chemokines and their receptors represent valuable targets for anti-inflammatory drug discovery. The N15P polypeptide (sequence: LGASWHRPDKCCLGY) is independently developed by our research group, it is a new CXCR4 antagonist drug derived from viral macrophage inflammatory protein-II (vMIP-II). This study aims to clarify the anti-inflammatory potency of N15P polypeptide on the lipopolysaccharide (LPS)-induced inflammation in vitro. In this study, we evaluated the anti-inflammatory effects of N15P polypeptide by the LPS-induced peripheral blood mononuclear cell (PBMC) model and measured the level of inflammatory factors (tumor necrosis factor alpha (TNF-α), IL-6, IL-8, nuclear factor kappaB (NF-κB), cyclooxygenase-2 (COX-2), Toll-like receptor 4 (TLR4), MyD88, phosphoinositide 3-kinase (PI3K), and Akt). The messenger RNA (mRNA) expressions of inflammatory factors were analyzed by real-time PCR (RT-PCR) microarray analysis, and the production of inflammatory factors was measured further by enzyme-linked immunosorbent assay (ELISA) and Western blot. The results showed that the expression of inflammatory factors (TNF-α, IL-6, IL-8, NF-κB, COX-2, TLR4, MyD88, PI3K, and Akt) was downregulated by N15P peptide, suggesting that N15P peptide has a strong inhibitory effect on the inflammatory responses induced by LPS.

  4. Anti‐Inflammatory Peptides From Cardiac Progenitors Ameliorate Dysfunction After Myocardial Infarction

    PubMed Central

    Liu, Mei‐Lan; Nagai, Toshio; Tokunaga, Masakuni; Iwanaga, Koji; Matsuura, Katsuhisa; Takahashi, Toshinao; Kanda, Masato; Kondo, Naomichi; Naito, Atsuhiko T.; Komuro, Issei; Kobayashi, Yoshio

    2014-01-01

    Background Cardiac cell therapy has been proposed as one of the new strategies against myocardial infarction. Although several reports showed improvement of the function of ischemic heart, the effects of cell therapy vary among the studies and the mechanisms of the beneficial effects are still unknown. Previously, we reported that clonal stem cell antigen‐1–positive cardiac progenitor cells exerted a therapeutic effect when transplanted into the ischemic heart. Our aims were to identify the cardiac progenitor‐specific paracrine factor and to elucidate the mechanism of its beneficial effect. Methods and Results By using an antibody array, we found that soluble junctional adhesion molecule‐A (JAM‐A) was abundantly secreted from cardiac progenitor cells. Pretreatment of neutrophils with conditioned medium from cultured cardiac progenitor cells or soluble JAM‐A inhibited transendothelial migration and reduced motility of neutrophils. These inhibitory effects were attenuated by anti–JAM‐A neutralizing antibody. Injection of cardiac progenitor cells into infarct heart attenuated neutrophil infiltration and expression of inflammatory cytokines. Injection of soluble JAM‐A–expressing, but not of JAM‐A siRNA–expressing, cardiac progenitor cells into the infarct heart prevented cardiac remodeling and reduced fibrosis area. Conclusions Soluble JAM‐A secreted from cardiac progenitor cells reduces infiltration of neutrophils after myocardial infarction and ameliorates tissue damage through prevention of excess inflammation. Our finding may lead to a new therapy for cardiovascular disease by using the anti‐inflammatory effect of JAM‐A. PMID:25468657

  5. A distinct multicytokine profile is associated with anti-cyclical citrullinated peptide antibodies in patients with early untreated inflammatory arthritis.

    PubMed

    Hitchon, Carol A; Alex, Philip; Erdile, Lawrence B; Frank, Mark B; Dozmorov, Igor; Tang, Yuhong; Wong, Keng; Centola, Michael; El-Gabalawy, Hani S

    2004-12-01

    Early inflammatory arthritis is clinically heterogenous and biologically-based indicators are needed to distinguish severe from self-limited disease. Anti-cyclical citrullinated peptides (CCP) have been identified as potential prognostic markers in early arthritis cohorts. Since cytokine networks are known to play a critical role in the pathogenesis of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, a panel of pro- and antiinflammatory cytokines was measured to identify biologically-based subsets of early arthritis, relating cytokine profiles to clinical measures and to the presence of RA-associated autoantibodies. Plasma concentrations of cytokines [interleukin 1beta (IL-1beta), IL-2, IL-4, IL-5, IL-6, IL-7, CXCL8 (IL-8), IL-10, IL-12p70, IL-13, IL-17, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-g (IFN-g), CCL2 (monocyte chemoattractant protein-1, MCP-1), CCL4 (MIP-1beta), and tumor necrosis factor-a (TNF-a)] were measured in patients with early, untreated inflammatory arthritis [symptom duration < or = 12 months; > or = 1 swollen joint; RA, n = 41; undifferentiated arthritis (UA), n = 23]. Cytokine expression patterns were determined using cluster analysis. Both pro- and antiinflammatory cytokines were elevated in patients over controls (n = 21). RA clustered into subgroups based solely on cytokine profiles. The "mild" RA subgroup (n = 23) had higher CCL4 (MIP-1beta), CXCL8 (IL-8), IL-2, IL-12, IL-17, IL-5, and IL-10 levels, lower IL-6, IFN-g, GM-CSF, and IL-4 levels, less CCP positivity (52% vs 82%; p < 0.05), and lower CCP titers [71 (78) vs 153 (94); p < 0.01], but similar erythrocyte sedimentation rate, C-reactive protein, and joint counts compared to the "severe" RA groups. CCL4 (MIP-1beta), IL-13, IL-12, TNF-a, and IL-4 best distinguished the groups. Combining UA with RA samples preserved cytokine subgroups and strengthened the autoantibody associations. Fewer UA

  6. The role of prokaryotes in supergene alteration of submarine hydrothermal sulfides

    NASA Astrophysics Data System (ADS)

    Glynn, S.; Mills, R. A.; Palmer, M. R.; Pancost, R. D.; Severmann, S.; Boyce, A. J.

    2006-04-01

    We combine mineralogical, stable isotope and organic biomarker data to understand the role of prokaryote activity in supergene reactions within submarine hydrothermal sulfidic sediments. Data are presented for two adjacent cores from the periphery of the inactive Alvin hydrothermal mound. The limit of oxygenated seawater penetration into the sulfidic sediments is expressed as a sharp peak in solid phase Cu (atacamite and secondary Cu sulfides) associated with supergene alteration of the sulfide pile. Total prokaryote numbers are low throughout the upper few metres of sediment relative to published data for deep-sea sites. However, there is a statistically significant enrichment of prokaryote numbers at the redox front that coincides with abundant Fe-oxide filaments and a unique distribution of microbial biomarkers. The dominance of quaternary-branched alkanes in the oxidized transition zone immediately above the redox front (and their absence below) suggests a significant role of the source organisms in iron or sulfide oxidation under the more circumneutral conditions associated with the redox transition zone. The morphology of the Fe-oxide filaments preserved within late stage silica and gypsum mineralization is consistent with a biogenic origin of the filaments. Gypsum sulfur isotopes are in equilibrium with fluids that are derived from quantitative sulfide oxidation and gypsum nucleation is inferred to be biologically induced. These new data suggest that supergene alteration of sulfidic sediments generates sharp redox and pH gradients that stimulate prokaryotic activity, in particular iron and sulfide oxidisers, which in turn govern the distribution of secondary mineral phases and the abundance of redox sensitive trace metals.

  7. Genes Outside the S Supergene Suppress S Functions in Buckwheat (Fagopyrum esculentum)

    PubMed Central

    MATSUI, K.; NISHIO, T.; TETSUKA, T.

    2004-01-01

    • Background and Aims Common buckwheat (Fagopyrum esculentum) is a dimorphic self-incompatible plant with either pin or thrum flowers. The S supergene is thought to govern self-incompatibility, flower morphology and pollen size in buckwheat. Two major types of self-fertile lines have been reported. One is a type with long-homostyle flowers, Kyukei SC2 (KSC2), and the other is a type with short-homostyle flowers, Pennline 10. To clarify whether the locus controlling flower morphology and self-fertility of Pennline 10 is the same as that of KSC2, pollen tube tests and genetic analysis have been performed. • Methods Pollen tube growth was assessed in the styles and flower morphology of KSC2, Pennline 10, F1 and F2 plants that were produced by the crosses between plants with pin or thrum and Pennline 10. • Key Results Pollen tubes of Pennline 10 reached ovules of all flower types. The flower morphology of F1 plants produced by the cross between thrum and Pennline 10 were thrum or pin, and when pin plants were used as maternal plants, all the F1 plants were pin. Both plants with pin or short-pin flowers, whose ratio of style length to anther height was smaller than that of pin, appeared in F2 populations of thrum × Pennline 10 as well as in those of pin × Pennline 10. • Conclusion The results suggest that Pennline 10 possesses the s allele as pin does, not an allele produced by the recombination in the S supergene, and that the short style length of Pennline 10 is controlled by multiple genes outside the S supergene. PMID:15465964

  8. Paleohydrologic evolution and geochemical dynamics of cumulative supergene metal enrichment at La Escondida, Atacama Desert, northern Chile

    USGS Publications Warehouse

    Alpers, C.N.; Brimhall, G.H.

    1989-01-01

    Quantitative limonite mapping within the leached capping of the porphyry copper deposit at La Escondida, Chile, permits reconstruction of the paleohydrologic and chemical evolution of a well-developed supergene ore-forming system. The mineralogy, textures, and relative abundance of supergene limonite minerals (hematite, goethite, and jarosite) are used to reconstruct the former ratio of pyrite to chalcocite and the preoxidation copper grade based on empirical limonite sulfide correlations. Evidence for cumulative downward enrichment in vertical profiles through leached capping allows quantitative analysis of chemical mass balance in dynamic supergene systems. Slopes of linear regressions for profiles of reconstructed enriched copper grades vs. depth indicate lateral fluxes into or out of a given vertical profile. -from Authors

  9. The modulation of inflammatory oedema by calcitonin gene-related peptide.

    PubMed Central

    Newbold, P.; Brain, S. D.

    1993-01-01

    1. The effect of calcitonin gene-related peptide (CGRP) when given with or as a pretreatment to oedema inducing agents was investigated in the skin and paws of male Wistar and Sprague Dawley rats. 2. Oedema formation at intradermally-injected sites in the skin was measured by a 125I-labelled human serum albumin accumulation technique and paw oedema was measured by a weight displacement technique. 3. CGRP (30 pmol) when given with, or as a 20 min pretreatment, markedly potentiated oedema formation induced by substance P (100 pmol) in rat skin. In comparison, CGRP had little effect on 5-hydroxytryptamine (5-HT, 0.1-3 nmol)-induced oedema when given as a co-injection but significantly potentiated 5-HT-induced oedema when given as a 20 min pretreatment in the skin. Similar results were obtained in both Wistar and Sprague Dawley rats. 4. Pretreatment with CGRP (30 pmol) had little modulatory effect on oedema induced by substance P (100 pmol) in the presence of the vasodilator prostanoid, prostaglandin E1 (PGE1, 850 pmol) in the skin of Wistar rats. 5. Pretreatment with CGRP (30 pmol) caused a non-significant increase in carrageenin (300 micrograms)-induced oedema in the hind paw of Wistar rats. Capsaicin (100 nmol) given as a pretreatment had little effect on carrageenin-induced oedema. 6. CGRP (30 pmol), given as a pretreatment, had little modulatory effect on 5-HT (3 nmol)-induced oedema in the paw of Wistar rats but a non-significant decrease in paw oedema was observed in Sprague Dawley rats.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7682134

  10. Apolipoprotein A-I mimetic peptide treatment inhibits inflammatory responses and improves survival in septic rats

    PubMed Central

    Zhang, Zhenghao; Datta, Geeta; Zhang, Yun; Miller, Andrew P.; Mochon, Paulina; Chen, Yiu-Fai; Chatham, John; Anantharamaiah, G. M.; White, C. Roger

    2009-01-01

    Systemic inflammation induces a multiple organ dysfunction syndrome that contributes to morbidity and mortality in septic patients. Since increasing plasma apolipoprotein A-I (apoA-I) and HDL may reduce the complications of sepsis, we tested the hypothesis that the apoA-I mimetic peptide 4F confers similar protective effects in rats undergoing cecal ligation and puncture (CLP) injury. Male Sprague-Dawley rats were randomized to undergo CLP or sham surgery. IL-6 levels were significantly elevated in plasma by 6 h after CLP surgery compared with shams. In subsequent studies, CLP rats were further subdivided to receive vehicle or 4F (10 mg/kg) by intraperitoneal injection, 6 h after sepsis induction. Sham-operated rats received saline. Echocardiographic studies showed a reduction in left ventricular end-diastolic volume, stroke volume, and cardiac output (CO) 24 h after CLP surgery. These changes were associated with reduced blood volume and left ventricular filling pressure. 4F treatment improved blood volume status, increased CO, and reduced plasma IL-6 in CLP rats. Total cholesterol (TC) and HDL were 79 ± 5 and 61 ± 4 mg/dl, respectively, in sham rats. TC was significantly reduced in CLP rats (54 ± 3 mg/dl) due to a reduction in HDL (26 ± 3 mg/dl). 4F administration to CLP rats attenuated the reduction in TC (69 ± 4 mg/dl) and HDL (41 ± 3 mg/dl) and prevented sepsis-induced changes in HDL protein composition. Increased plasma HDL in 4F-treated CLP rats was associated with an improvement in CO and reduced mortality. It is proposed that protective effects of 4F are related to its ability to prevent the sepsis-induced reduction in plasma HDL. PMID:19561306

  11. Development and characterization of targeted poly(NIPAm) nanoparticles for delivery of anti-inflammatory peptides in peripheral artery disease and osteoarthritis

    NASA Astrophysics Data System (ADS)

    McMasters, James F.

    Inflammation is the underlying cause of several severe diseases including cardiovascular disease and osteoarthritis. Peripheral artery disease (PAD) is characterized by atherosclerotic occlusions within the peripheral vasculature. Current treatment for severe PAD involves mechanical widening of the artery via percutaneous transluminal angioplasty. Unfortunately, deployment of the balloon damages the endothelial layer, exposing the underlying collagenous matrix. Circulating platelets can bind to this collagen and become activated, releasing proinflammatory cytokines that promote proliferation of local smooth muscle cells. These proliferating cells eventually reocclude the vessel, resulting in restenosis and necessitating the need for a second procedure to reopen the vessel. Current treatments for moderate osteoarthritis include local injection of anti-inflammatory compounds such as glucocorticoids. Unfortunately, prolonged treatment carries with it significant side effects including osteoporosis, and cardiovascular complications. Our lab has developed an anti-inflammatory cell-penetrating peptide that inhibits mitogen-activated protein kinase activated protein kinase 2 (MK2). MK2 is implicated in the inflammatory cascade of atherosclerosis and osteoarthritis, making it a potentially effective strategy for reducing inflammation in both disease states. Unfortunately, these peptides are untargeted and quickly degraded in the presence of serum proteases, making the development of an effective delivery system of paramount importance. The overall goal of the research presented here is to detail the development of a poly(N-isopropylacrylamide) nanoparticle that is able to effectively load and release anti-inflammatory peptides for the treatment of these inflammatory diseases. In this dissertation, I will discuss the development of a collagen-binding nanoparticle that is able to inhibit platelet binding following angioplasty, thereby halting the initial inflammatory cascade

  12. Homeostatic regulation of T cell trafficking by a B cell derived peptide is impaired in autoimmune and chronic inflammatory disease

    PubMed Central

    Apta, Bonita; Kuravi, Sahithi J.; Yates, Clara M.; Kennedy, Amy; Odedra, Arjun; Alassiri, Mohammed; Harrison, Matthew; Martin, Ashley; Barone, Francesca; Nayar, Saba; Hitchcock, Jessica R.; Cunningham, Adam F.; Raza, Karim; Filer, Andrew; Copland, David A.; Dick, Andrew D.; Robinson, Joseph; Kalia, Neena; Walker, Lucy S. K.; Buckley, Christopher D.; Nash, Gerard B.; Narendran, Parth; Rainger, G. Ed.

    2015-01-01

    During an inflammatory response, lymphocyte recruitment into tissue must be tightly controlled because dysregulated trafficking contributes to the pathogenesis of chronic disease. Here we show that during inflammation and in response to adiponectin, B cells tonically inhibit T cell trafficking by secreting a peptide (PEPITEM) proteolytically derived from 14.3.3.ζδ protein. PEPITEM binds cadherin-15 on endothelial cells, promoting synthesis and release of sphingosine-1 phosphate, which inhibits trafficking of T cells without affecting recruitment of other leukocytes. Expression of adiponectin receptors on B cells and adiponectin induced PEPITEM secretion wanes with age, implying immune senescence of the pathway. Additionally, these changes are evident in individuals with type-1-diabetes or rheumatoid arthritis, and circulating PEPITEM in patient serum is reduced compared to healthy age matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Importantly, control of patient T cell trafficking is re-established by exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic I/R injury, Salmonella infection, Uveitis and Sjögren’s Syndrome, PEPITEM could reduce T cell recruitment into inflamed tissues. PMID:25894827

  13. Elevated serum procollagen type III peptide in splanchnic and peripheral circulation of patients with inflammatory bowel disease submitted to surgery

    PubMed Central

    De Simone, Matilde; Cioffi, Ugo; Contessini-Avesani, Ettore; Oreggia, Barbara; Paliotti, Roberta; Pierini, Alberto; Bolla, Gianni; Oggiano, Elide; Ferrero, Stefano; Magrini, Fabio; Ciulla, Michele M

    2004-01-01

    Background In the hypothesis that the increased collagen metabolism in the intestinal wall of patients affected by inflammatory bowel disease (IBD) is reflected in the systemic circulation, we aimed the study to evaluate serum level of procollagen III peptide (PIIIP) in peripheral and splanchnic circulation by a commercial radioimmunoassay of patients with different histories of disease. Methods Twenty-seven patients, 17 with Crohn and 10 with ulcerative colitis submitted to surgery were studied. Blood samples were obtained before surgery from a peripheral vein and during surgery from the mesenteric vein draining the affected intestinal segment. Fifteen healthy age and sex matched subjects were studied to determine normal range for peripheral PIIIP. Results In IBD patients peripheral PIIIP level was significantly higher if compared with controls (5.0 ± 1.9 vs 2.7 ± 0.7 μg/l; p = 0.0001); splanchnic PIIIP level was 5.5 ± 2.6 μg/l showing a positive gradient between splanchnic and peripheral concentrations of PIIIP. No significant differences between groups nor correlations with patients' age and duration of disease were found. Conclusions We provide evidence that the increased local collagen metabolism in active IBD is reflected also in the systemic circulation irrespective of the history of the disease, suggesting that PIIIP should be considered more appropiately as a marker of the activity phases of IBD. PMID:15527511

  14. Glucagon-Like Peptide-1-Mediated Modulation of Inflammatory Pathways in the Diabetic Brain: Relevance to Alzheimer's Disease.

    PubMed

    Qin, LiMei; Chong, Thomas; Rodriguez, Richard; Pugazhenthi, Subbiah

    2016-01-01

    Neuroinflammation has emerged as an important cause of cognitive decline during aging and in Alzheimer's disease (AD). Chronic low-grade inflammation is observed in obesity and diabetes, which are important risk factors for AD. Therefore, we examined the markers of inflammation in the brain hippocampal samples of Zucker diabetic fatty (ZDF) rats. Pathway-specific gene expression profiling revealed significant increases in the expression of oxidative stress and inflammatory genes. Western blot analysis further showed the activation of NF-kB, defective CREB phosphorylation, and decreases in the levels of neuroprotective CREB target proteins, including Bcl-2, BDNF, and BIRC3 in the diabetic rat brain samples, all of which are related to AD pathology. As therapies based on glucagon-like peptide-1 (GLP-1) are effective in controlling blood glucose levels in type 2 diabetic patients, we tested the in vivo actions of GLP-1 in the diabetic brain by a 10-wk treatment of ZDF rats with alogliptin, an inhibitor of dipeptidyl peptidase. Alogliptin increased the circulating levels of GLP-1 by 125% and decreased blood glucose in diabetic rats by 59%. Normalization of defective signaling to CREB in the hippocampal samples of treated diabetic rats resulted in the increased expression of CREB targets. Dual actions of GLP-1 in the pancreatic beta cells and in the brain suggest that incretin therapies may reduce cognitive decline in the aging diabetic patients and also have the potential to be used in treating Alzheimer's patients.

  15. Genetic architecture and evolution of the S locus supergene in Primula vulgaris.

    PubMed

    Li, Jinhong; Cocker, Jonathan M; Wright, Jonathan; Webster, Margaret A; McMullan, Mark; Dyer, Sarah; Swarbreck, David; Caccamo, Mario; Oosterhout, Cock van; Gilmartin, Philip M

    2016-12-02

    Darwin's studies on heterostyly in Primula described two floral morphs, pin and thrum, with reciprocal anther and stigma heights that promote insect-mediated cross-pollination. This key innovation evolved independently in several angiosperm families. Subsequent studies on heterostyly in Primula contributed to the foundation of modern genetic theory and the neo-Darwinian synthesis. The established genetic model for Primula heterostyly involves a diallelic S locus comprising several genes, with rare recombination events that result in self-fertile homostyle flowers with anthers and stigma at the same height. Here we reveal the S locus supergene as a tightly linked cluster of thrum-specific genes that are absent in pins. We show that thrums are hemizygous not heterozygous for the S locus, which suggests that homostyles do not arise by recombination between S locus haplotypes as previously proposed. Duplication of a floral homeotic gene 51.7 million years (Myr) ago, followed by its neofunctionalization, created the current S locus assemblage which led to floral heteromorphy in Primula. Our findings provide new insights into the structure, function and evolution of this archetypal supergene.

  16. Androgen alleviates neurotoxicity of β-amyloid peptide (Aβ) by promoting microglial clearance of Aβ and inhibiting microglial inflammatory response to Aβ.

    PubMed

    Yao, Peng-Le; Zhuo, Shu; Mei, Hong; Chen, Xiao-Fang; Li, Na; Zhu, Teng-Fei; Chen, Shi-Ting; Wang, Ji-Ming; Hou, Rui-Xing; Le, Ying-Ying

    2017-11-01

    Lower androgen level in elderly men is a risk factor of Alzheimer's disease (AD). It has been reported that androgen reduces amyloid peptides (Aβ) production and increases Aβ degradation by neurons. Activated microglia are involved in AD by either clearing Aβ deposits through uptake of Aβ or releasing cytotoxic substances and pro-inflammatory cytokines. Here, we investigated the effect of androgen on Aβ uptake and clearance and Aβ-induced inflammatory response in microglia, on neuronal death induced by Aβ-activated microglia, and explored underlying mechanisms. Intracellular and extracellular Aβ were examined by immunofluorescence staining and Western blot. Amyloid peptides (Aβ) receptors, Aβ degrading enzymes, and pro-inflammatory cytokines were detected by RT-PCR, real-time PCR, and ELISA. Phosphorylation of MAP kinases and NF-κB was examined by Western blot. We found that physiological concentrations of androgen enhanced Aβ42 uptake and clearance, suppressed Aβ42 -induced IL-1β and TNFα expression by murine microglia cell line N9 and primary microglia, and alleviated neuronal death induced by Aβ42 -activated microglia. Androgen administration also reduced Aβ42 -induced IL-1β expression and neuronal death in murine hippocampus. Mechanistic studies revealed that androgen promoted microglia to phagocytose and degrade Aβ42 through upregulating formyl peptide receptor 2 and endothelin-converting enzyme 1c expression, and inhibited Aβ42 -induced pro-inflammatory cytokines expression via suppressing MAPK p38 and NF-κB activation by Aβ42 , in an androgen receptor independent manner. Our study demonstrates that androgen promotes microglia to phagocytose and clear Aβ42 and inhibits Aβ42 -induced inflammatory response, which may play an important role in reducing the neurotoxicity of Aβ. © 2017 John Wiley & Sons Ltd.

  17. Long-term stability of anti-cyclic citrullinated peptide antibody status in patients with early inflammatory polyarthritis.

    PubMed

    Burr, Marian L; Viatte, Sebastien; Bukhari, Marwan; Plant, Darren; Symmons, Deborah P; Thomson, Wendy; Barton, Anne

    2012-05-09

    The utility of reassessing anti-cyclic citrullinated peptide (anti-CCP) antibody status later in disease in patients presenting with early undifferentiated inflammatory polyarthritis, particularly in those who test negative for both anti-CCP and rheumatoid factor (RF) at baseline, remains unclear. We aimed therefore to determine the stability of CCP antibody status over time and the prognostic utility of repeated testing in subjects with early inflammatory polyarthritis (IP). Anti-CCP and RF were measured at baseline and 5 years in 640 IP patients from the Norfolk Arthritis Register, a primary care-based inception cohort. The relation between change in anti-CCP status/titer and the presence of radiologic erosions, the extent of the Larsen score, and Health Assessment Questionnaire (HAQ) score by 5 years was investigated. With a cut-off of 5 U/ml, 28% subjects tested positive for anti-CCP antibodies, 29% for RF, and 21% for both at baseline. Nine (2%) anti-CCP-negative patients seroconverted to positive, and nine (4.6%) anti-CCP-positive individuals became negative between baseline and 5 years. In contrast, RF status changed in 17% of subjects. However, change in RF status was strongly linked to baseline anti-CCP status and was not independently associated with outcome. Ever positivity for anti-CCP antibodies by 5 years did not improve prediction of radiographic damage compared with baseline status alone (accuracy, 75% versus 74%). A higher baseline anti-CCP titer (but not change in anti-CCP titer) predicted worse radiologic damage at 5 years (P < 0.0001), even at levels below the cut-off for anti-CCP positivity. Thus, a titer of 2 to 5 U/ml was strongly associated with erosions by 5 years (odds ratio, 3.6 (1.5 to 8.3); P = 0.003). Repeated testing of anti-CCP antibodies or RF in patients with IP does not improve prognostic value and should not be recommended in routine clinical practice.

  18. Elevated pro-brain natriuretic peptide, troponin T and malnutrition inflammatory score in chronic hemodialysis patients with overt cardiovascular disease.

    PubMed

    Trimarchi, Hernán; Muryan, Alexis; Campolo-Girard, Vicente; Dicugno, Mariana; Barucca, Nanci; Lombi, Fernando; Young, Pablo; Pomeranz, Vanesa; Forrester, Mariano; Alonso, Mirta; Iriarte, Romina; Díaz, Marisa Luisa; Lindholm, Bengt

    2011-01-01

    We assessed the relationship between pro-brain natriuretic peptide (pro-BNP), troponin T (TropT) and nutritional status. A total of 48 chronic hemodialysis patients were grouped according to the presence [group A (GA); n = 24] or not [group B (GB)] of cardiovascular disease. Compared to GB subjects, GA subjects were older, had been on hemodialysis for a longer period and had higher prevalences of vascular grafts, hypertension and elevated C-reactive protein (CRP) [GA vs. GB: 1.1 (range 0.1-32.9) vs. 0.4 (0-28.1) mg/dl; p = 0.028], malnutrition inflammatory score (MIS) (GA vs. GB: 7.50 vs. 4.00; p = 0.001), pro-BNP [GA vs. GB: 6,760 (601-103,200) vs. 686 (75-83,700) pg/ml; p < 0.001] and TropT [GA vs. GB: 0.3650 (0.011-0.199) vs. 0.010 (0.0-0.290) ng/ml; p = 0.002]. Pro-BNP correlated with TropT (rho 0.539; p < 0.001), MIS (rho 0.502; p < 0.0001), homocysteine (rho 0.321; p = 0.13) and CRP (rho 0.511; p < 0.0001). Pro-BNP levels were lower in GB patients as the body mass index increased; the opposite occurred in GA. Patients with cardiovascular disease had elevated pro-BNP and TropT levels. In patients without cardiovascular disease, malnutrition and inflammation were associated with vascular prostheses, while pro-BNP was lower in obese patients. Copyright © 2010 S. Karger AG, Basel.

  19. Hydrostatin-TL1, an Anti-Inflammatory Active Peptide from the Venom Gland of Hydrophis cyanocinctus in the South China Sea

    PubMed Central

    Wang, Ningyuan; Huang, Yan; Li, An; Jiang, Hailong; Wang, Jie; Li, Jianzhong; Qiu, Lei; Li, Ka; Lu, Yiming

    2016-01-01

    Tumor necrosis factor (TNF)-α is a pleiotropic cytokine with intense pro-inflammatory and immunomodulatory properties, and anti-TNF-α biologics are effective therapies for various inflammatory diseases such as inflammatory bowel disease (IBD) and sepsis. Snake venom, as a traditional Chinese medicine, has been used in the treatment of inflammatory diseases in China for centuries. In this research, we constructed a venom gland T7 phage display library of the sea snake Hydrophis cyanocinctus to screen bioactive compounds that antagonize TNF-α and identified a novel nine-amino-acid peptide, termed hydrostatin-TL1 (H-TL1). In enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) analyses, H-TL1 inhibited the interaction between TNF-α and TNF receptor 1 (TNFR1). Further, H-TL1 attenuated the cytotoxicity of TNF-α in L929 cells as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. H-TL1 also decreased the mRNA expression of TNF-α/TNFR1 downstream targets and suppressed the phosphorylation of well-characterized proteins of downstream signal transduction pathways in HEK-293 cells. In vivo data demonstrated that H-TL1 protects animals against dextran sodium sulfate (DSS)-induced acute colitis and lipopolysaccharide (LPS)-induced acute shock. Given its significant anti-inflammatory activity in vitro and in vivo, H-TL1 is a potential peptide for the development of new agents to treat TNF-α-associated inflammatory diseases. PMID:27879679

  20. Hydrostatin-TL1, an Anti-Inflammatory Active Peptide from the Venom Gland of Hydrophis cyanocinctus in the South China Sea.

    PubMed

    Wang, Ningyuan; Huang, Yan; Li, An; Jiang, Hailong; Wang, Jie; Li, Jianzhong; Qiu, Lei; Li, Ka; Lu, Yiming

    2016-11-22

    Tumor necrosis factor (TNF)-α is a pleiotropic cytokine with intense pro-inflammatory and immunomodulatory properties, and anti-TNF-α biologics are effective therapies for various inflammatory diseases such as inflammatory bowel disease (IBD) and sepsis. Snake venom, as a traditional Chinese medicine, has been used in the treatment of inflammatory diseases in China for centuries. In this research, we constructed a venom gland T7 phage display library of the sea snake Hydrophis cyanocinctus to screen bioactive compounds that antagonize TNF-α and identified a novel nine-amino-acid peptide, termed hydrostatin-TL1 (H-TL1). In enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) analyses, H-TL1 inhibited the interaction between TNF-α and TNF receptor 1 (TNFR1). Further, H-TL1 attenuated the cytotoxicity of TNF-α in L929 cells as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. H-TL1 also decreased the mRNA expression of TNF-α/TNFR1 downstream targets and suppressed the phosphorylation of well-characterized proteins of downstream signal transduction pathways in HEK-293 cells. In vivo data demonstrated that H-TL1 protects animals against dextran sodium sulfate (DSS)-induced acute colitis and lipopolysaccharide (LPS)-induced acute shock. Given its significant anti-inflammatory activity in vitro and in vivo, H-TL1 is a potential peptide for the development of new agents to treat TNF-α-associated inflammatory diseases.

  1. Therapeutic Effect of Ergotope Peptides on Collagen-Induced Arthritis by Downregulation of Inflammatory and Th1/Th17 Responses and Induction of Regulatory T Cells

    PubMed Central

    Niu, Xiaoyin; Deng, Shaohua; Li, Shan; Xi, Yebin; Li, Chengzhen; Wang, Li; He, Dongyi; Wang, Zhaojun; Chen, Guangjie

    2016-01-01

    Rheumatoid arthritis (RA) is a systemic autoimmune disease that results in a chronic and inflammatory disorder. Dynamic balance of helper T cells (Th) 1 and 17 and regulatory T cells (Treg) is broken in RA. Since there is no cure for RA at present, it is necessary to find a truly effective and convenient treatment. Several studies have intended to induce ergotopic regulation to treat autoimmune diseases. This study was undertaken to find potential ergotope peptides and investigate their effects in treating the animal model of RA and their underlying regulatory mechanisms. First, we selected functional ergotope peptides from 25 overlapping peptides derived from the interleukin 2 receptor (IL-2R) α chain, and then used these peptides to treat collagen-induced arthritis (CIA). We showed ergotope peptides as immunomodulatory factors with great benefits at the clinical and pathologic levels. This effect was associated with inhibition of type II collagen (CII)-specific proliferation and autoantibody production as well as induction of antiergotypic immune response, downregulation of both Th1 and Th17 cells and their related components, and emergence of Treg cells that had suppressive action on autoreactive T cells. We also proved that cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) and IL-10 are two important mediators that are critical to Treg suppressive function. Inhibition of Th1 and Th17 in established CIA could be attributed to ergotope-induced Treg cells. Our findings reveal that ergotope peptides induce regulatory immune responses and restore immune tolerance, suggesting that treatment with ergotope peptides may be a novel approach to therapy for RA patients and has good application prospects, with cheap, effective, convenient, wide-spectrum features. PMID:27579476

  2. Novel Insights into the Cellular Mechanisms of the Anti-inflammatory Effects of NF-κB Essential Modulator Binding Domain Peptides

    PubMed Central

    Baima, Eric T.; Guzova, Julia A.; Mathialagan, Sumathy; Nagiec, Eva E.; Hardy, Medora M.; Song, Lily R.; Bonar, Sheri L.; Weinberg, Robin A.; Selness, Shaun R.; Woodard, Scott S.; Chrencik, Jill; Hood, William F.; Schindler, John F.; Kishore, Nandini; Mbalaviele, Gabriel

    2010-01-01

    The classical nuclear factor κB (NF-κB) signaling pathway is under the control of the IκB kinase (IKK) complex, which consists of IKK-1, IKK-2, and NF-κB essential modulator (NEMO). This complex is responsible for the regulation of cell proliferation, survival, and differentiation. Dysregulation of this pathway is associated with several human diseases, and as such, its inhibition offers an exciting opportunity for therapeutic intervention. NEMO binding domain (NBD) peptides inhibit the binding of recombinant NEMO to IKK-2 in vitro. However, direct evidence of disruption of this binding by NBD peptides in biological systems has not been provided. Using a cell system, we expanded on previous observations to show that NBD peptides inhibit inflammation-induced but not basal cytokine production. We report that these peptides cause the release of IKK-2 from an IKK complex and disrupt NEMO-IKK-2 interactions in cells. We demonstrate that by interfering with NEMO-IKK-2 interactions, NBD peptides inhibit IKK-2 phosphorylation, without affecting signaling intermediates upstream of the IKK complex of the NF-κB pathway. Furthermore, in a cell-free system of IKK complex activation by TRAF6 (TNF receptor-associated factor 6), we show that these peptides inhibit the ability of this complex to phosphorylate downstream substrates, such as p65 and inhibitor of κBα (IκBα). Thus, consistent with the notion that NEMO regulates IKK-2 catalytic activity by serving as a scaffold, appropriately positioning IKK-2 for activation by upstream kinase(s), our findings provide novel insights into the molecular mechanisms by which NBD peptides exert their anti-inflammatory effects in cells. PMID:20167598

  3. Therapeutic effect of ergotope peptides on CIA by down-regulation of inflammatory and Th1/Th17 responses and induction of regulatory T cells.

    PubMed

    Niu, Xiaoyin; Deng, Shaohua; Li, Shan; Xi, Yebin; Li, Chengzhen; Wang, Li; He, Dongyi; Wang, Zhaojun; Chen, Guangjie

    2016-08-30

    Rheumatoid arthritis (RA) is a systemic autoimmune disease that results in a chronic and inflammatory disorder. Dynamic balance of helper T cells (Th)1, Th17 and regulatory T cells (Treg) is broken in RA. Since there is no cure for RA at present, it's necessary to find a truly effective and convenient treatment. Several studies intended to induce ergotopic regulation to treat autoimmune diseases. This study was undertaken to find the potential ergotope peptides and investigate its effect in treating the animal model of RA and their underlying regulatory mechanisms. Firstly, we selected the functional ergotope peptides from 25 overlapping peptides derived from interlukin(IL)-2 receptor (IL-2R) α chain, and then used these peptides to treat collagen-induced arthritis (CIA). The study showed ergotope peptides as immunomodulatory factors with great benefits at the clinical and pathologic levels. This effect was associated with the inhibition of type II collagen (CII)-specific proliferation and autoantibody production as well as the induction of anti-ergotypic immune response, the down-regulation of both Th1 and Th17 cells and their related components, and the emergence of Treg cells that had suppressive actions on autoreactive T cells. We also proved that cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and IL-10 are two important mediators which are critical to Treg suppressive function. The inhibition of Th1 and Th17 in established CIA could be attributed to ergotope induced Treg cells. Our findings reveal that ergotope peptides induce regulatory immune responses and restore immune tolerance, suggesting ergotope peptides treatment appears to be a novel approach to the therapy of RA patients and has a good application prospect with cheap, effective, convenient, wide-spectrum features.

  4. Supergene leaching and formation of platinum in alluvium: evidence from Serro, Minas Gerais, Brazil

    NASA Astrophysics Data System (ADS)

    Cabral, A. R.; Beaudoin, G.; Choquette, M.; Lehmann, B.; Polônia, J. C.

    2007-05-01

    The Córrego Bom Sucesso alluvial deposit near Serro, Minas Gerais, probably provided the specimens from which the element palladium was first discovered. Its Pt-Pd nuggets are characteristically botryoidal, arborescent and coralloidal, and exhibit an external halo with the composition of palladiferous platinum to virtually pure platinum. X-ray mapping of an arborescent Pt-Pd nugget from the historical occurrence documents selective palladium depletion, similar to the high-fineness gold haloes developed on detrital Au-Ag grains under supergene conditions. The Pd-depleted alteration zone truncates inclusions of crystals stoichiometrically close to PdPt within the Pt-Pd aggregate. Selective metal leaching in the weathering environment can account for the frequently observed Pt-enriched rims on alluvial platiniferous alloys which may lead to the formation of platinum nuggets at an advanced degree of weathering.

  5. A Single Dose of the Anti-Resorptive Peptide Human Calcitonin Paradoxically Augments Particle- and Endotoxin-Mediated Pro-Inflammatory Cytokine Production In Vitro.

    PubMed

    Jablonski, H; Wedemeyer, C; Bachmann, H S; Schlagkamp, M; Bernstein, A; Jäger, M; Kauther, M D

    2016-09-01

    The peptide hormone calcitonin (CT) is known to inhibit bone resorption and has previously been shown also to prevent particle-induced osteolysis, the leading cause of revision arthroplasty. In the present study, the influence of human CT on the initial inflammatory response to particulate wear debris or bacterial endotoxins, ultimately leading to osteoclast-mediated bone resorption, was analysed in human THP-1 macrophage-like cells. The cells were activated with either ultra-high molecular weight polyethylene (UHMWPE) particles or bacterial lipopolysaccharides (LPS) in order to simulate an osteolysis-associated inflammatory response. The cells were simultaneously treated with human CT (10(-9) M). Cytokine production of tumour necrosis factor (TNF)-α was quantified on both RNA and protein levels while interleukins (IL)-1β and IL-6 were measured as secreted protein only. Stimulation of the cells with either particles or LPS led to a dose- and time-dependent increase of TNF-α mRNA production and protein secretion of TNF-α, IL-1β, and IL-6. Application of CT mostly enhanced cytokine production as elicited by UHMWPE particles while a pronounced transient inhibitory effect on LPS-induced inflammation became evident at 24 h of incubation. Human CT displayed ambivalent effects on the wear- and LPS-induced production of pro-inflammatory cytokines. Thereby, the peptide primarily upregulated particle-induced inflammation while LPS-induced cytokine secretion was temporarily attenuated in a distinct manner. It needs to be evaluated whether the pro- or anti-inflammatory action of CT contributes to its known anti-resorptive effects. Thus, the therapeutic potential of the peptide in the treatment of either particle- or endotoxin-mediated bone resorption could be determined. © Georg Thieme Verlag KG Stuttgart · New York.

  6. The anti-inflammatory peptide stearyl-norleucine-VIP delays disease onset and extends survival in a rat model of inherited amyotrophic lateral sclerosis.

    PubMed

    Goursaud, Stéphanie; Schäfer, Sabrina; Dumont, Amélie O; Vergouts, Maxime; Gallo, Alessandro; Desmet, Nathalie; Deumens, Ronald; Hermans, Emmanuel

    2015-01-01

    Vasoactive intestinal peptide (VIP) has potent immune modulatory actions that may influence the course of neurodegenerative disorders associated with chronic inflammation. Here, we show the therapeutic benefits of a modified peptide agonist stearyl-norleucine-VIP (SNV) in a transgenic rat model of amyotrophic lateral sclerosis (mutated superoxide dismutase 1, hSOD1(G93A)). When administered by systemic every-other-day intraperitoneal injections during a period of 80 days before disease, SNV delayed the onset of motor dysfunction by no less than three weeks, while survival was extended by nearly two months. SNV-treated rats showed reduced astro- and microgliosis in the lumbar ventral spinal cord and a significant degree of motor neuron preservation. Throughout the treatment, SNV promoted the expression of the anti-inflammatory cytokine interleukin-10 as well as neurotrophic factors commonly considered as beneficial in amyotrophic lateral sclerosis management (glial derived neuroptrophic factor, insulin like growth factor, brain derived neurotrophic factor). The peptide nearly totally suppressed the expression of tumor necrosis factor-α and repressed the production of the pro-inflammatory mediators interleukin-1β, nitric oxide and of the transcription factor nuclear factor kappa B. Inhibition of tumor necrosis factor-α likely accounted for the observed down-regulation of nuclear factor kappa B that modulates the transcription of genes specifically involved in amyotrophic lateral sclerosis (sod1 and the glutamate transporter slc1a2). In line with this, levels of human superoxide dismutase 1 mRNA and protein were decreased by SNV treatment, while the expression and activity of the glutamate transporter-1 was promoted. Considering the large diversity of influences of this peptide on both clinical features of the disease and associated biochemical markers, we propose that SNV or related peptides may constitute promising candidates for amyotrophic lateral sclerosis

  7. Effects of antimicrobial peptide L-K6, a temporin-1CEb analog on oral pathogen growth, Streptococcus mutans biofilm formation, and anti-inflammatory activity.

    PubMed

    Shang, Dejing; Liang, Hao; Wei, Shi; Yan, Xin; Yang, Qingzu; Sun, Yue

    2014-10-01

    Dental caries and periodontitis are common bacterial mouth infections. As a potentially attractive substitute for conventional antibiotics, antimicrobial peptides have been widely tested and used for controlling bacterial infections. In this study, we tested the efficacy of the peptides from the skin secretions of Rana chensinensis for killing several major cariogenic and periodontic pathogens as well as Candida albicans. L-K6, a temporin-1CEb analog, exhibited high antimicrobial activity against the tested oral pathogens and was able to inhibit Streptococcus mutans biofilm formation and reduce 1-day-old S. mutans biofilms with a minimum biofilm inhibitory concentration and reducing concentration of 3.13 and 6.25 μM, respectively. The results of confocal laser scanning microscopy demonstrated that the peptide significantly reduced cell viability within oral biofilms. Furthermore, as little as 5 μM L-K6 significantly inhibited lipopolysaccharide (LPS)- and interleukin-1β-induced productions of interleukin-8 and tumor necrosis factor-α from THP-1 monocytic cells. This anti-inflammatory activity is associated with the binding of L-K6 to LPS and neutralizing LPS-induced proinflammatory responses in THP-1 cells, as well as dissociating LPS aggregates. Our results suggest that L-K6 may have potential clinical applications in treating dental caries by killing S. mutans within dental plaque and acting as anti-inflammatory agents in infected tissues.

  8. Annexin A1 released from apoptotic cells acts through formyl peptide receptors to dampen inflammatory monocyte activation via JAK/STAT/SOCS signalling

    PubMed Central

    Pupjalis, Danute; Goetsch, Julia; Kottas, Diane J; Gerke, Volker; Rescher, Ursula

    2011-01-01

    The immunosuppressive effects of apoptotic cells involve inhibition of pro-inflammatory cytokine release and establishment of an anti-inflammatory cytokine profile, thus limiting the degree of inflammation and promoting resolution. We report here that this is in part mediated by the release of the anti-inflammatory mediator annexin A1 from apoptotic cells and the functional activation of annexin A1 receptors of the formyl peptide receptor (FPR) family on target cells. Supernatants from apoptotic neutrophils or the annexin A1 peptidomimetic Ac2-26 significantly reduced IL-6 signalling and the release of TNF-α from endotoxin-challenged monocytes. Ac2-26 activated STAT3 in a JAK-dependent manner, resulting in upregulated SOCS3 levels, and depletion of SOCS3 reversed the Ac2-26-mediated inhibition of IL-6 signalling. This identifies annexin A1 as part of the anti-inflammatory pattern of apoptotic cells and links the activation of FPRs to established signalling pathways triggering anti-inflammatory responses. PMID:21254404

  9. High Fat Diet Alters Gut Microbiota and the Expression of Paneth Cell-Antimicrobial Peptides Preceding Changes of Circulating Inflammatory Cytokines

    PubMed Central

    Li, Jinchao; Tang, Renyong; Zhang, Guodong; Zeng, Huawei; Wood, Richard J.

    2017-01-01

    Obesity is an established risk factor for many diseases including intestinal cancer. One of the responsible mechanisms is the chronic inflammation driven by obesity. However, it remains to be defined whether diet-induced obesity exacerbates the intestinal inflammatory status by cytokines produced in adipose tissue or the high fat diet first alters the gut microbiota and then drives intestinal inflammation. To address this question, we fed C57BL/6 mice with a high fat diet (HF, 60%) and sacrificed them sequentially after 8, 12, and 16 weeks, and then compositions of gut microbiota and expressions of antimicrobial peptides were determined. The compositions of gut microbiota were altered at 8 wk HF feeding, followed with reduced Paneth antimicrobial peptides lysozyme and Reg IIIγ after 12 and 16 wk HF feeding (p < 0.05), whereas elevations of circulating inflammatory cytokines IFNγ and TNF-α were observed until feeding a HF diet for 16 weeks (p < 0.05). These results indicated that high fat diet may stimulate intestinal inflammation via altering gut microbiota, and it occurs prior to the potential influence by circulating inflammatory cytokines. These findings emphasized the importance of microbiota, in addition to adipose tissue per se, in driving intestinal inflammation, which may thereafter promote intestinal tumorigenesis. PMID:28316379

  10. High Fat Diet Alters Gut Microbiota and the Expression of Paneth Cell-Antimicrobial Peptides Preceding Changes of Circulating Inflammatory Cytokines.

    PubMed

    Guo, Xiulan; Li, Jinchao; Tang, Renyong; Zhang, Guodong; Zeng, Huawei; Wood, Richard J; Liu, Zhenhua

    2017-01-01

    Obesity is an established risk factor for many diseases including intestinal cancer. One of the responsible mechanisms is the chronic inflammation driven by obesity. However, it remains to be defined whether diet-induced obesity exacerbates the intestinal inflammatory status by cytokines produced in adipose tissue or the high fat diet first alters the gut microbiota and then drives intestinal inflammation. To address this question, we fed C57BL/6 mice with a high fat diet (HF, 60%) and sacrificed them sequentially after 8, 12, and 16 weeks, and then compositions of gut microbiota and expressions of antimicrobial peptides were determined. The compositions of gut microbiota were altered at 8 wk HF feeding, followed with reduced Paneth antimicrobial peptides lysozyme and Reg IIIγ after 12 and 16 wk HF feeding (p < 0.05), whereas elevations of circulating inflammatory cytokines IFNγ and TNF-α were observed until feeding a HF diet for 16 weeks (p < 0.05). These results indicated that high fat diet may stimulate intestinal inflammation via altering gut microbiota, and it occurs prior to the potential influence by circulating inflammatory cytokines. These findings emphasized the importance of microbiota, in addition to adipose tissue per se, in driving intestinal inflammation, which may thereafter promote intestinal tumorigenesis.

  11. Benefit of early treatment in inflammatory polyarthritis patients with anti–cyclic citrullinated peptide antibodies versus those without antibodies

    PubMed Central

    Farragher, Tracey M; Lunt, Mark; Plant, Darren; Bunn, Diane K; Barton, Anne; Symmons, Deborah P M

    2010-01-01

    Objective To compare the clinical utility of anti–cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) testing in predicting both functional outcome and response to treatment in early inflammatory polyarthritis (IP) patients. Methods A total of 916 IP subjects from a primary care incidence registry (1990–1994) had anti-CCP antibody and RF status determined at baseline. Mean change in Health Assessment Questionnaire (HAQ) score between baseline and 5 years was compared by antibody status. The effect of treatment with disease-modifying antirheumatic drugs and/or steroids over 5 years, early (<6 months of symptom onset) versus late initiation, and duration of treatment were also compared by anti-CCP antibody status. The analysis was adjusted for treatment decisions and censoring over the followup, using marginal structural models. Results Anti-CCP antibody–positive patients (n = 268) had more severe disease both at presentation and 5 years of followup, and this was independent of RF. On adjustment, anti-CCP antibody–negative patients treated early experienced a significant improvement in functional disability compared with anti-CCP antibody–negative patients who were never treated (−0.31; 95% confidence interval [95% CI] −0.53, −0.08), and experienced additional benefit for each additional month of early treatment. Anti-CCP antibody–positive patients treated early did not have a significant improvement in HAQ score compared with those not treated (−0.14; 95% CI −0.52, 0.24). Conclusion In this first observational study to examine the influence of anti-CCP antibody status on treatment response, anti-CCP antibody–positive IP patients showed less benefit from treatment, particularly early treatment, than anti-CCP antibody–negative patients. This provides support for the inclusion of anti-CCP antibodies as well as RF in the classification criteria for rheumatoid arthritis and for stratification by anti-CCP antibody status

  12. Antibodies to mutated citrullinated vimentin and anti-cyclic citrullinated peptide antibodies in inflammatory bowel disease and related arthritis.

    PubMed

    Al-Jarallah, Khaled; Shehab, Diaa; Al-Attiyah, Rajaa; Al-Azmi, Waleed; Al-Fadli, Ahmad; Zafar Haider, Mohammed; Panaccione, Remo; Ghosh, Subrata

    2012-09-01

    Antibodies that react with citrullinated proteins (anti-mutated citrullinated vimentin [anti-MCV] and second-generation anti-cyclic citrullinated peptide antibodies [anti-CCP2]) are markers for rheumatoid arthritis. Recent studies have demonstrated that these antibodies are present in other arthropathies including the spondyloarthritis, psoriatic arthritis, and juvenile idiopathic arthritis. Arthritis associated with inflammatory bowel disease (IBD) takes various forms, with some shared similarities with classic spondylarthropathies. Our objective was to investigate the role of anti-MCV and anti-CCP2 as potential biomarkers in IBD and related arthritis. In all, 125 IBD patients (71 males, 54 females) were compared to 81 age- and sex-matched healthy controls. Anti-MCV and Anti-CCP2 IgG were measured using an enzyme linked immunosorbent assay. In the 125 IBD patients (mean age 32.6 ± 12.3 years), 44 (35.2%) had ulcerative colitis and 81 (64.8%) had Crohn's disease. Forty-four (35.2%) IBD patients developed arthritic manifestations. Antibody positivity was observed in 24/125 (19.2%) IBD patients and in 18/81 (22.2%) healthy subjects. The proportion of anti-MCV positivity among IBD patients and healthy individuals were similar: 16.8% vs. 16.0%, P = 0.887. Anti-CCP2 positivity among IBD patients and healthy individuals was also comparable: 6.4% vs. 6.2%, P = 0.948. Similarly, the presence of anti-MCV and anti-CCP2 antibodies was not different among IBD patients with and without arthritis. The mean titers of antibodies were low: anti-MCV (29.6 ± 7.5 U/mL) and anti-CCP2 (27.6 ± 4.0 U/mL) in IBD patients with arthritis. Autoantibodies to citrullinated proteins were low in IBD-related arthritis. These findings suggest that these antibodies are not useful biomarkers in IBD to predict who may develop IBD-related arthropathy. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.

  13. Conjugation of curcumin-loaded lipid nanoemulsions with cell-penetrating peptides increases their cellular uptake and enhances the anti-inflammatory effects in endothelial cells.

    PubMed

    Simion, Viorel; Stan, Daniela; Constantinescu, Cristina Ana; Deleanu, Mariana; Dragan, Emanuel; Tucureanu, Monica Madalina; Gan, Ana-Maria; Butoi, Elena; Constantin, Alina; Manduteanu, Ileana; Simionescu, Maya; Calin, Manuela

    2016-02-01

    To prepare and characterize in vitro and in vivo lipid nanoemulsions (LN) loaded with curcumin (Cm) and functionalized with a cell-penetrating peptide. Curcumin-loaded lipid nanoemulsions (CmLN) functionalized with a nona-arginine peptide (R9-CmLN) have been obtained, characterized and optimized for size, entrapment efficiency and in vitro Cm release. The interaction of R9-CmLN with human endothelial cells (HEC) was investigated using cultured EA.hy926 cells, and in vivo biodistribution studies were performed using C57BL6 mice. When used in therapeutically relevant concentration, R9-CmLN have low haemolytic activity, low cytotoxicity on HEC, and show anti-inflammatory effects by reducing the monocytes adhesion to TNF-α activated HEC. Moreover, HEC uptake and internalization of R9-CmLN was significantly higher compared to the non-functionalized CmLN. In vivo biodistribution studies in mice revealed a higher accumulation of R9-CmLN in the liver and the lungs compared to CmLN and the body clearance of the both nanoformulations after 72 h. Cell-penetrating peptides-functionalized CmLN have superior characteristics compared to their non-functionalized counterparts: are more efficiently internalized by the cells, produces anti-inflammatory effects in HEC and when administrated intravenously in mice exhibit increased accumulation in the liver and the lungs, suggesting their potential therapeutic applications in different inflammatory pathologies localized in the liver or the lungs. © 2016 Royal Pharmaceutical Society.

  14. A structure-activity relationship of non-peptide macrocyclic histone deacetylase inhibitors and their anti-proliferative and anti-inflammatory activities.

    PubMed

    Tapadar, Subhasish; Fathi, Shaghayegh; Raji, Idris; Omesiete, Wilson; Kornacki, James R; Mwakwari, Sandra C; Miyata, Masanori; Mitsutake, Kazunori; Li, Jian-Dong; Mrksich, Milan; Oyelere, Adegboyega K

    2015-12-15

    Inhibition of the enzymatic activity of histone deacetylase (HDAC) is a promising therapeutic strategy for cancer treatment and several distinct small molecule histone deacetylase inhibitors (HDACi) have been reported. We have previously identified a new class of non-peptide macrocyclic HDACi derived from 14- and 15-membered macrolide skeletons. In these HDACi, the macrocyclic ring is linked to the zinc chelating hydroxamate moiety through a para-substituted aryl-triazole cap group. To further delineate the depth of the SAR of this class of HDACi, we have synthesized series of analogous compounds and investigated the influence of various substitution patterns on their HDAC inhibitory, anti-proliferative and anti-inflammatory activities. We identified compounds 25b and 38f with robust anti-proliferative activities and compound 26f (IC50 47.2 nM) with superior anti-inflammatory (IC50 88 nM) activity relative to SAHA. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. The kiwi fruit peptide kissper displays anti-inflammatory and anti-oxidant effects in in-vitro and ex-vivo human intestinal models.

    PubMed

    Ciacci, C; Russo, I; Bucci, C; Iovino, P; Pellegrini, L; Giangrieco, I; Tamburrini, M; Ciardiello, M A

    2014-03-01

    Literature reports describe kiwi fruit as a food with significant effects on human health, including anti-oxidant and anti-inflammatory activity. Fresh fruit or raw kiwi fruit extracts have been used so far to investigate these effects, but the molecule(s) responsible for these health-promoting activities have not yet been identified. Kissper is a kiwi fruit peptide displaying pore-forming activity in synthetic lipid bilayers, the composition of which is similar to that found in intestinal cells. The objective of this study was to investigate the kissper influence on intestinal inflammation using cultured cells and ex-vivo tissues from healthy subjects and Crohn's disease (CD) patients. The anti-oxidant and anti-inflammatory properties of kissper were tested on Caco-2 cells and on the colonic mucosa from 23 patients with CD, by challenging with the lipopolysaccharide from Escherichia coli (EC-LPS) and monitoring the appropriate markers by Western blot and immunofluorescence. EC-LPS challenge determined an increase in the intracellular concentration of calcium and reactive oxygen species (ROS). The peptide kissper was highly effective in preventing the increase of LPS-induced ROS levels in both the Caco-2 cells and CD colonic mucosa. Moreover, it controls the calcium increase, p65-nuclear factor (NF)-kB induction and transglutaminase 2 (TG2) activation inflammatory response in Caco-2 cells and CD colonic mucosa. Kissper efficiently counteracts the oxidative stress and inflammatory response in valuable model systems consisting of intestinal cells and CD colonic mucosa. This study reports the first evidence supporting a possible correlation between some beneficial effects of kiwi fruit and a specific protein molecule rather than generic nutrients.

  16. An antisense peptide nucleic acid against Pseudomonas aeruginosa inhibiting bacterial-induced inflammatory responses in the cystic fibrosis IB3-1 cellular model system.

    PubMed

    Montagner, Giulia; Bezzerri, Valentino; Cabrini, Giulio; Fabbri, Enrica; Borgatti, Monica; Lampronti, Ilaria; Finotti, Alessia; Nielsen, Peter E; Gambari, Roberto

    2017-02-03

    Discovery of novel antimicrobial agents against Pseudomonas aeruginosa able to inhibit bacterial growth as well as the resulting inflammatory response is a key goal in cystic fibrosis research. We report in this paper that a peptide nucleic acid (PNA3969) targeting the translation initiation region of the essential acpP gene of P. aeruginosa, and previously shown to inhibit bacterial growth, concomitantly also strongly inhibits PAO1 induced up-regulation of the pro-inflammatory markers IL-8, IL-6, G-CSF, IFN-γ, IP-10, MCP-1 and TNF-α in IB3-1 cystic fibrosis cells infected by P. aeruginosa PAO1. Remarkably, no effect on PAO1 induction of VEGF, GM-CSF and IL-17 was observed. Analogous experiments using a two base mis-match control PNA did not show such inhibition. Furthermore, no significant effects of the PNAs were seen on cell growth, apoptosis or secretome profile in uninfected IB3-1 cells (with the exception of a PNA-mediated up-regulation of PDGF, IL-17 and GM-CSF). Thus, we conclude that in cell culture an antimicrobial PNA against Pseudomonas can inhibit the expression of pro-inflammatory cytokines otherwise induced by the infection. In particular, the effects of PNA-3969 on IL-8 gene expression are significant considering the key role of this protein in the cystic fibrosis inflammatory process exacerbated by P. aeruginosa infection.

  17. Screening of an anti-inflammatory peptide from Hydrophis cyanocinctus and analysis of its activities and mechanism in DSS-induced acute colitis

    PubMed Central

    Zheng, Zengjie; Jiang, Hailong; Huang, Yan; Wang, Jie; Qiu, Lei; Hu, Zhenlin; Ma, Xingyuan; Lu, Yiming

    2016-01-01

    Snake has been used for centuries as a traditional Chinese medicine, especially for therapeutic treatment for inflammatory diseases; however, its mechanisms of action and active constituents remain controversial. In our study, a tumor necrosis factor receptor 1 (TNFR1) selective binding peptide, Hydrostatin-SN1 (H-SN1), which was screened from a Hydrophis cyanocinctus venom gland T7 phage display library, was shown to exhibit significant anti-inflammatory activity in vitro and in vivo. As a TNFR1 antagonist, it reduced cytotoxicity mediated by TNF-α in L929 fibroblasts and effectively inhibited the combination between TNF-α with TNFR1 in surface plasmon resonance analysis. H-SN1 was also shown to suppress TNFR1–associated signaling pathways as it minimized TNF-α-induced NF-кB and MAPK activation in HEK293 embryonic kidney and HT29 adenocarcinoma cell lines. We next determined the effect of H-SN1 in vivo using a murine model of acute colitis induced by dextran sodium sulfate, demonstrating that H-SN1 lowered the clinical parameters of acute colitis including the disease activity index and histologic scores. H-SN1 also inhibited TNF/TNFR1 downstream targets at both mRNA and protein levels. These results indicate that H-SN1 might represent a suitable candidate for use in the treatment of TNF-α-associated inflammatory diseases such as inflammatory bowel diseases. PMID:27158082

  18. Antimicrobial and anti-inflammatory activities of three chensinin-1 peptides containing mutation of glycine and histidine residues

    PubMed Central

    Dong, Weibing; Mao, Xiaoman; Guan, Yue; Kang, Yao; Shang, Dejing

    2017-01-01

    The natural peptide chensinin-1 doesnot exhibit its desired biological properties. In this study, the mutant MC1-1 was designed by replacing Gly in the chensinin-1 sequence with Trp. Mutants MC1-2 and MC1-3 were designed based on the MC1-1 sequence to investigate the specific role of His residues. The mutated peptides presented α-helicity in a membrane-mimetic environment and exhibited broad-spectrum antimicrobial activities; in contrast to Trp residues, His residues were dispensable for interacting with the cell membrane. The interactions between the mutant peptides and lipopolysaccharide (LPS) facilitated the ingestion of peptides by Gram-negative bacteria. The binding affinities of the peptides were similar, at approximately 10 μM, but ΔH for MC1-2 was −7.3 kcal.mol−1, which was 6-9 folds higher than those of MC1-1 and MC1-3, probably due to the conformational changes. All mutant peptides demonstrated the ability to inhibit LPS-induced tumour-necrosis factor-α (TNF-α) and interleukin-6 (IL-6) release from murine RAW264.7 cells. In addition, the representative peptide MC1-1showed better inhibition of serum TNF-α and IL-6 levels compared to polymyxin B (PMB), a potent binder and neutralizer of LPS as positive control in LPS-challenged mice model. These data suggest that the mutant peptides could be promising molecules for development as chensinin-based therapeutic agents against sepsis. PMID:28054660

  19. Anti-inflammatory peptide regulates the supply of heat shock protein 70 monomers: implications for aging and age-related disease.

    PubMed

    Cunningham, Timothy J; Greenstein, Jeffrey I; Loewenstern, Joshua; Degermentzidis, Elias; Yao, Lihua

    2015-04-01

    Reducing the levels of toxic protein aggregates has become a focus of therapy for disorders like Alzheimer's and Parkinson's diseases, as well as for the general deterioration of cells and tissues during aging. One approach has been an attempt to influence the production or activity of a class of reparative chaperones called heat shock proteins (HSPs), of which HSP70 is a promising candidate. Manipulation of HSP70 expression results in disposal of misfolded protein aggregates that accumulate in aging and disease models. Recently, HSP70 has been shown to bind specifically to an amino-terminal sequence of a human diffusible survival evasion peptide (DSEP), dermcidin. This sequence includes CHEC-9, an orally available anti-inflammatory and cell survival peptide. In the present study, we found that the CHEC-9 peptide also binds HSP70 in the cytosol of the cerebral cortex after oral delivery in normal rats. Western analysis of non-heat-denatured, unreduced samples suggested that peptide treatment increased the level of active HSP70 monomers from the pool of chaperone oligomers, a process that may be stimulated by potentiation of the chaperone's adenosine triphosphatase (ATPase). In these samples, a small but consistent gel shift was observed for glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a multifunctional protein whose aggregation is influenced by HSP70. CHEC-9 treatment of an in vitro model of α-synuclein aggregation also results in HSP70-dependent dissolution of these aggregates. HSP70 oligomer-monomer equilibrium and its potential to control protein aggregate disease warrant increased experimental attention, especially if a peptide fragment of an endogenous human protein can influence the process.

  20. Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers

    PubMed Central

    Cobb, Laura J.; Lee, Changhan; Xiao, Jialin; Yen, Kelvin; Wong, Richard G.; Nakamura, Hiromi K.; Mehta, Hemal H.; Gao, Qinglei; Ashur, Carmel; Huffman, Derek M.; Wan, Junxiang; Muzumdar, Radhika; Barzilai, Nir; Cohen, Pinchas

    2016-01-01

    Mitochondria are key players in aging and in the pathogenesis of age-related diseases. Recent mitochondrial transcriptome analyses revealed the existence of multiple small mRNAs transcribed from mitochondrial DNA (mtDNA). Humanin (HN), a peptide encoded in the mtDNA 16S ribosomal RNA region, is a neuroprotective factor. An in silico search revealed six additional peptides in the same region of mtDNA as humanin; we named these peptides small humanin-like peptides (SHLPs). We identified the functional roles for these peptides and the potential mechanisms of action. The SHLPs differed in their ability to regulate cell viability in vitro. We focused on SHLP2 and SHLP3 because they shared similar protective effects with HN. Specifically, they significantly reduced apoptosis and the generation of reactive oxygen species, and improved mitochondrial metabolism in vitro. SHLP2 and SHLP3 also enhanced 3T3-L1 pre-adipocyte differentiation. Systemic hyperinsulinemic-euglycemic clamp studies showed that intracerebrally infused SHLP2 increased glucose uptake and suppressed hepatic glucose production, suggesting that it functions as an insulin sensitizer both peripherally and centrally. Similar to HN, the levels of circulating SHLP2 were found to decrease with age. These results suggest that mitochondria play critical roles in metabolism and survival through the synthesis of mitochondrial peptides, and provide new insights into mitochondrial biology with relevance to aging and human biology. PMID:27070352

  1. Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers.

    PubMed

    Cobb, Laura J; Lee, Changhan; Xiao, Jialin; Yen, Kelvin; Wong, Richard G; Nakamura, Hiromi K; Mehta, Hemal H; Gao, Qinglei; Ashur, Carmel; Huffman, Derek M; Wan, Junxiang; Muzumdar, Radhika; Barzilai, Nir; Cohen, Pinchas

    2016-04-01

    Mitochondria are key players in aging and in the pathogenesis of age-related diseases. Recent mitochondrial transcriptome analyses revealed the existence of multiple small mRNAs transcribed from mitochondrial DNA (mtDNA). Humanin (HN), a peptide encoded in the mtDNA 16S ribosomal RNA region, is a neuroprotective factor. An in silico search revealed six additional peptides in the same region of mtDNA as humanin; we named these peptides small humanin-like peptides (SHLPs). We identified the functional roles for these peptides and the potential mechanisms of action. The SHLPs differed in their ability to regulate cell viability in vitro. We focused on SHLP2 and SHLP3 because they shared similar protective effects with HN. Specifically, they significantly reduced apoptosis and the generation of reactive oxygen species, and improved mitochondrial metabolism in vitro. SHLP2 and SHLP3 also enhanced 3T3-L1 pre-adipocyte differentiation. Systemic hyperinsulinemic-euglycemic clamp studies showed that intracerebrally infused SHLP2 increased glucose uptake and suppressed hepatic glucose production, suggesting that it functions as an insulin sensitizer both peripherally and centrally. Similar to HN, the levels of circulating SHLP2 were found to decrease with age. These results suggest that mitochondria play critical roles in metabolism and survival through the synthesis of mitochondrial peptides, and provide new insights into mitochondrial biology with relevance to aging and human biology.

  2. Attenuation of monocyte chemotaxis--a novel anti-inflammatory mechanism of action for the cardio-protective hormone B-type natriuretic peptide.

    PubMed

    Glezeva, Nadezhda; Collier, Patrick; Voon, Victor; Ledwidge, Mark; McDonald, Kenneth; Watson, Chris; Baugh, John

    2013-08-01

    B-type natriuretic peptide (BNP) is a prognostic and diagnostic marker for heart failure (HF). An anti-inflammatory, cardio-protective role for BNP was proposed. In cardiovascular diseases including pressure overload-induced HF, perivascular inflammation and cardiac fibrosis are, in part, mediated by monocyte chemoattractant protein (MCP)1-driven monocyte migration. We aimed to determine the role of BNP in monocyte motility to MCP1. A functional BNP receptor, natriuretic peptide receptor-A (NPRA) was identified in human monocytes. BNP treatment inhibited MCP1-induced THP1 (monocytic leukemia cells) and primary monocyte chemotaxis (70 and 50 %, respectively). BNP did not interfere with MCP1 receptor expression or with calcium. BNP inhibited activation of the cytoskeletal protein RhoA in MCP1-stimulated THP1 (70 %). Finally, BNP failed to inhibit MCP1-directed motility of monocytes from patients with hypertension (n = 10) and HF (n = 6) suggesting attenuation of this anti-inflammatory mechanism in chronic heart disease. We provide novel evidence for a direct role of BNP/NPRA in opposing human monocyte migration and support a role for BNP as a cardio-protective hormone up-regulated as part of an adaptive compensatory response to combat excess inflammation.

  3. The Insect Peptide CopA3 Increases Colonic Epithelial Cell Proliferation and Mucosal Barrier Function to Prevent Inflammatory Responses in the Gut*

    PubMed Central

    Kim, Dae Hong; Hwang, Jae Sam; Lee, Ik Hwan; Nam, Seung Taek; Hong, Ji; Zhang, Peng; Lu, Li Fang; Lee, Junguee; Seok, Heon; Pothoulakis, Charalabos; Lamont, John Thomas; Kim, Ho

    2016-01-01

    The epithelial cells of the gut form a physical barrier against the luminal contents. The collapse of this barrier causes inflammation, and its therapeutic restoration can protect the gut against inflammation. EGF enhances mucosal barrier function and increases colonocyte proliferation, thereby ameliorating inflammatory responses in the gut. Based on our previous finding that the insect peptide CopA3 promotes neuronal growth, we herein tested whether CopA3 could increase the cell proliferation of colonocytes, enhance mucosal barrier function, and ameliorate gut inflammation. Our results revealed that CopA3 significantly increased epithelial cell proliferation in mouse colonic crypts and also enhanced colonic epithelial barrier function. Moreover, CopA3 treatment ameliorated Clostridium difficile toxin As-induced inflammation responses in the mouse small intestine (acute enteritis) and completely blocked inflammatory responses and subsequent lethality in the dextran sulfate sodium-induced mouse model of chronic colitis. The marked CopA3-induced increase of colonocyte proliferation was found to require rapid protein degradation of p21Cip1/Waf1, and an in vitro ubiquitination assay revealed that CopA3 directly facilitated ubiquitin ligase activity against p21Cip1/Waf1. Taken together, our findings indicate that the insect peptide CopA3 prevents gut inflammation by increasing epithelial cell proliferation and mucosal barrier function. PMID:26655716

  4. The Insect Peptide CopA3 Increases Colonic Epithelial Cell Proliferation and Mucosal Barrier Function to Prevent Inflammatory Responses in the Gut.

    PubMed

    Kim, Dae Hong; Hwang, Jae Sam; Lee, Ik Hwan; Nam, Seung Taek; Hong, Ji; Zhang, Peng; Lu, Li Fang; Lee, Junguee; Seok, Heon; Pothoulakis, Charalabos; Lamont, John Thomas; Kim, Ho

    2016-02-12

    The epithelial cells of the gut form a physical barrier against the luminal contents. The collapse of this barrier causes inflammation, and its therapeutic restoration can protect the gut against inflammation. EGF enhances mucosal barrier function and increases colonocyte proliferation, thereby ameliorating inflammatory responses in the gut. Based on our previous finding that the insect peptide CopA3 promotes neuronal growth, we herein tested whether CopA3 could increase the cell proliferation of colonocytes, enhance mucosal barrier function, and ameliorate gut inflammation. Our results revealed that CopA3 significantly increased epithelial cell proliferation in mouse colonic crypts and also enhanced colonic epithelial barrier function. Moreover, CopA3 treatment ameliorated Clostridium difficile toxin As-induced inflammation responses in the mouse small intestine (acute enteritis) and completely blocked inflammatory responses and subsequent lethality in the dextran sulfate sodium-induced mouse model of chronic colitis. The marked CopA3-induced increase of colonocyte proliferation was found to require rapid protein degradation of p21(Cip1/Waf1), and an in vitro ubiquitination assay revealed that CopA3 directly facilitated ubiquitin ligase activity against p21(Cip1/Waf1). Taken together, our findings indicate that the insect peptide CopA3 prevents gut inflammation by increasing epithelial cell proliferation and mucosal barrier function.

  5. Genomic Analysis of Detoxification Supergene Families in the Mosquito Anopheles sinensis

    PubMed Central

    Zhou, Dan; Liu, Xianmiao; Sun, Yan; Ma, Lei; Shen, Bo; Zhu, Changliang

    2015-01-01

    Anopheles sinensis is an important malaria vector in China and other Southeast Asian countries, and the emergence of insecticide resistance in this mosquito poses a serious threat to the efficacy of malaria control programs. The recently published An. sinensis genome and transcriptome provide an opportunity to understand the molecular mechanisms of insecticide resistance. Analysis of the An. sinensis genome revealed 174 detoxification genes, including 93 cytochrome P450s (P450s), 31 glutathione-S-transferases (GSTs), and 50 choline/carboxylesterases (CCEs). The gene number was similar to that in An. gambiae, but represented a decrease of 29% and 42% compared with Aedes aegypti and Culex quinquefasciatus, respectively. The considerable contraction in gene number in Anopheles mosquitoes mainly occurred in two detoxification supergene families, P450s and CCEs. The available An. sinensis transcriptome was also re-analyzed to further identify key resistance-associated detoxification genes. Among 174 detoxification genes, 124 (71%) were detected. Several candidate genes overexpressed in a deltamethrin-resistant strain (DR-strain) were identified as belonging to the CYP4 or CYP6 family of P450s and the Delta GST class. These generated data provide a basis for identifying the resistance-associated genes of An. sinensis at the molecular level. PMID:26588704

  6. Polymorphism at a mimicry supergene maintained by opposing frequency-dependent selection pressures.

    PubMed

    Chouteau, Mathieu; Llaurens, Violaine; Piron-Prunier, Florence; Joron, Mathieu

    2017-08-01

    Explaining the maintenance of adaptive diversity within populations is a long-standing goal in evolutionary biology, with important implications for conservation, medicine, and agriculture. Adaptation often leads to the fixation of beneficial alleles, and therefore it erodes local diversity so that understanding the coexistence of multiple adaptive phenotypes requires deciphering the ecological mechanisms that determine their respective benefits. Here, we show how antagonistic frequency-dependent selection (FDS), generated by natural and sexual selection acting on the same trait, maintains mimicry polymorphism in the toxic butterfly Heliconius numata Positive FDS imposed by predators on mimetic signals favors the fixation of the most abundant and best-protected wing-pattern morph, thereby limiting polymorphism. However, by using mate-choice experiments, we reveal disassortative mate preferences of the different wing-pattern morphs. The resulting negative FDS on wing-pattern alleles is consistent with the excess of heterozygote genotypes at the supergene locus controlling wing-pattern variation in natural populations of H. numata The combined effect of positive and negative FDS on visual signals is sufficient to maintain a diversity of morphs displaying accurate mimicry with other local prey, although some of the forms only provide moderate protection against predators. Our findings help understand how alternative adaptive phenotypes can be maintained within populations and emphasize the need to investigate interactions between selective pressures in other cases of puzzling adaptive polymorphism.

  7. A supergene determines highly divergent male reproductive morphs in the ruff

    PubMed Central

    dos Remedios, Natalie; Farrell, Lindsay L.; McRae, Susan B.; Morgan, Tawna C.; Karlionova, Natalia; Pinchuk, Pavel; Verkuil, Yvonne I.; Kitaysky, Alexander S.; Wingfield, John C.; Piersma, Theunis; Zeng, Kai; Slate, Jon; Blaxter, Mark; Lank, David B.; Burke, Terry

    2015-01-01

    Three strikingly different alternative male mating morphs (aggressive “Independents”, semi-cooperative “Satellites” and female mimic “Faeders”) coexist as a balanced polymorphism in the ruff, Philomachus pugnax, a lek-breeding wading bird1,2,3. Major differences in body size, ornamentation, and aggressive and mating behaviour are inherited as an autosomal polymorphism4,5. We show that development into Satellites and Faeders is determined by a supergene6,7,8 consisting of divergent alternative, dominant, non-recombining haplotypes of an inversion on chromosome 11, which contains 125 predicted genes. Independents are homozygous for the ancestral sequence. One breakpoint of the inversion disrupts the essential Centromere protein N (CENP-N) gene, and pedigree analysis confirms lethality of inversion homozygotes. We describe novel behavioural, testes size, and steroid metabolic differences among morphs, and identify polymorphic genes within the inversion that are likely to contribute to the differences among morphs in reproductive traits. PMID:26569125

  8. Synthetic antimicrobial and LPS-neutralising peptides suppress inflammatory and immune responses in skin cells and promote keratinocyte migration

    PubMed Central

    Pfalzgraff, Anja; Heinbockel, Lena; Su, Qi; Gutsmann, Thomas; Brandenburg, Klaus; Weindl, Günther

    2016-01-01

    The stagnation in the development of new antibiotics and the concomitant high increase of resistant bacteria emphasize the urgent need for new therapeutic options. Antimicrobial peptides are promising agents for the treatment of bacterial infections and recent studies indicate that Pep19-2.5, a synthetic anti-lipopolysaccharide (LPS) peptide (SALP), efficiently neutralises pathogenicity factors of Gram-negative (LPS) and Gram-positive (lipoprotein/-peptide, LP) bacteria and protects against sepsis. Here, we investigated the potential of Pep19-2.5 and the structurally related compound Pep19-4LF for their therapeutic application in bacterial skin infections. SALPs inhibited LP-induced phosphorylation of NF-κB p65 and p38 MAPK and reduced cytokine release and gene expression in primary human keratinocytes and dermal fibroblasts. In LPS-stimulated human monocyte-derived dendritic cells and Langerhans-like cells, the peptides blocked IL-6 secretion, downregulated expression of maturation markers and inhibited dendritic cell migration. Both SALPs showed a low cytotoxicity in all investigated cell types. Furthermore, SALPs markedly promoted cell migration via EGFR transactivation and ERK1/2 phosphorylation and accelerated artificial wound closure in keratinocytes. Peptide-induced keratinocyte migration was mediated by purinergic receptors and metalloproteases. In contrast, SALPs did not affect proliferation of keratinocytes. Conclusively, our data suggest a novel therapeutic target for the treatment of patients with acute and chronic skin infections. PMID:27509895

  9. Vasoactive Intestinal Peptide Down-Regulates Pro- While Up-Regulating Anti-Inflammatory Toll-like Receptors in the Infected Cornea

    PubMed Central

    Jiang, Xiaoyu; McClellan, Sharon A.; Barrett, Ronald P.; Zhang, Yunfan; Hazlett, Linda D.

    2012-01-01

    Toll-like receptors (TLRs) recognize microbial pathogens and trigger an immune response, but their regulation by neuropeptides such as vasoactive intestinal peptide (VIP) during Pseudomonas aeruginosa corneal infection remains unexplored. Therefore, C57BL/6 (B6) mice were injected intraperitoneally with VIP and mRNA, protein and immunostaining assays done. After VIP treatment PCR array and real-time RT-PCR demonstrated that pro-inflammatory TLRs (Chuk, IRAK1, TLR1, 4, 6, 8, 9 and TRAF6) were down-regulated, while anti-inflammatory TLRs (SIGIRR and ST2) were up-regulated. ELISA showed that VIP modestly down-regulated phosphorylated IKKα, but up-regulated ST2 almost 2 fold. SIGIRR also was up-regulated, while TLR4 immunostaining was reduced in cornea; all confirming the mRNA data. To determine if VIP effects were cAMP dependent, mice were injected with siRNA for type 7 adenylate cyclase (AC7) with or without VIP treatment. After silencing AC7, changes in mRNA levels of TLR1, TRAF6 and ST2 were seen and unchanged with addition of VIP, indicating their regulation was cAMP dependent. In contrast, changes were seen in mRNA levels of Chuk, IRAK1, 2, TLR4, 9 and SIGIRR following AC7 silencing alone, which were modified by VIP addition, indicating their cAMP independence. In vitro studies tested the effects of VIP on TLR regulation in macrophages and Langerhans cells. VIP down-regulated mRNA expression of pro-inflammatory, while up-regulating anti-inflammatory TLRs in both cell types. Collectively, the data provide evidence that VIP down-regulates pro- and up-regulates anti-inflammatory TLRs, that this regulation is both cAMP dependent and independent, and involves immune cell types found in the infected cornea. PMID:22661083

  10. Anti-atherogenic and anti-inflammatory properties of glucagon-like peptide-1, glucose-dependent insulinotropic polypepide, and dipeptidyl peptidase-4 inhibitors in experimental animals.

    PubMed

    Hirano, Tsutomu; Mori, Yusaku

    2016-04-01

    We reported that native incretins, liraglutide and dipeptidyl peptidase-4 inhibitors (DPP-4i) all confer an anti-atherosclerotic effect in apolipoprotein E-null (Apoe (-/-)) mice. We confirmed the anti-atherogenic property of incretin-related agents in the mouse wire injury model, in which the neointimal formation in the femoral artery is remarkably suppressed. Furthermore, we showed that DPP-4i substantially suppresses plaque formation in coronary arteries with a marked reduction in the accumulation of macrophages in cholesterol-fed rabbits. DPP-4i showed an anti-atherosclerotic effect in Apoe (-/-) mice mainly through the actions of glucagon-like peptide-1 and glucose-dependent insulinotropic polypepide. However, the dual incretin receptor antagonists partially attenuated the suppressive effect of DPP-4i on atherosclerosis in diabetic Apoe (-/-) mice, suggesting an incretin-independent mechanism. Exendin-4 and glucose-dependent insulinotropic polypepide elicited cyclic adenosine monophosphate generation, and suppressed the lipopolysaccharide-induced gene expression of inflammatory molecules, such as interleukin-1β, interleukin-6 and tumor necrosis factor-α, in U937 human monocytes. This suppressive effect, however, was attenuated by an inhibitor of adenylate cyclase and mimicked by 8-bromo-cyclic adenosine monophosphate or forskolin. DPP-4i substantially suppressed the lipopolysaccharide-induced expression of inflammatory cytokines without affecting cyclic adenosine monophosphate generation or cell proliferation. DPP-4i more strongly suppressed the lipopolysaccharide-induced gene expression of inflammatory molecules than incretins, most likely through inactivation of CD26. Glucagon-like peptide-1 and glucose-dependent insulinotropic polypepide suppressed oxidized low-density lipoprotein-induced macrophage foam cell formation in a receptor-dependent manner, which was associated with the downregulation of acyl-coenzyme A cholesterol acyltransferase-1 and CD36, as

  11. A multifunctional alanine-rich anti-inflammatory peptide BCP61 showed potent inhibitory effects by inhibiting both NF-κB and MAPK expression.

    PubMed

    Choi, Yun Hee; Choi, Yoon Seok; Kim, Young Kyun; Rahman, Md Saifur; Pradeep, G C; Yoo, Jin Cheol; Suh, Joo-Won

    2017-04-01

    The purified BCP61 was reported to be a unique low-molecular-weight (MW) anti-microbial peptide because of its non-identical alanine-rich N-terminal sequence. In this study, we investigated the anti-inflammatory effects of BCP61 on induction of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), pro-inflammatory cytokines, nuclear factor-kappa B (NF-κB), and mitogen-activated protein kinases (MAPKs) in lipopolysaccharide (LPS)-stimulated Raw 264.7 cells. The treatment with BCP61, with varying concentrations of 10, 50, and 100 μg/mL, inhibited levels of expression of LPS-induced NF-κB and MAPKs (extracellular signal-related kinases (ERKs), c-Jun NH2-terminal kinase (JNK), and mitogen-activated protein (p38)) as well as production of pro-inflammatory mediators, such as nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). The results suggested that BCP61 prevents inhibitor of kappa B (IκBα) phosphorylation and degradation, thereby inhibiting the nuclear translocation of the p65 protein. We do report that the use of BCP61 in the treatment of inflammation as well as microbial infection could be a potent therapeutic candidate.

  12. Sustained release of hepatocyte growth factor by cationic self-assembling peptide/heparin hybrid hydrogel improves β-cell survival and function through modulating inflammatory response

    PubMed Central

    Liu, Shuyun; Zhang, Lanlan; Cheng, Jingqiu; Lu, Yanrong; Liu, Jingping

    2016-01-01

    Inflammatory response is a major cause of grafts dysfunction in islet transplantation. Hepatocyte growth factor (HGF) had shown anti-inflammatory activity in multiple diseases. In this study, we aim to deliver HGF by self-assembling peptide/heparin (SAP/Hep) hybrid gel to protect β-cell from inflammatory injury. The morphological and slow release properties of SAPs were analyzed. Rat INS-1 β-cell line was treated with tumor necrosis factor α in vitro and transplanted into rat kidney capsule in vivo, and the viability, apoptosis, function, and inflammation of β-cells were evaluated. Cationic KLD1R and KLD2R self-assembled to nanofiber hydrogel, which showed higher binding affinity for Hep and HGF because of electrostatic interaction. Slow release of HGF from cationic SAP/Hep gel is a two-step mechanism involving binding affinity with Hep and molecular diffusion. In vitro and in vivo results showed that HGF-loaded KLD2R/Hep gel promoted β-cell survival and insulin secretion, and inhibited cell apoptosis, cytokine release, T-cell infiltration, and activation of NFκB/p38 MAPK pathways in β-cells. This study suggested that SAP/Hep gel is a promising carrier for local delivery of bioactive proteins in islet transplantation. PMID:27729786

  13. The monocyte locomotion inhibitory factor an anti-inflammatory peptide; therapeutics originating from amebic abscess of the liver.

    PubMed

    Velazquez, Juan R

    2011-01-01

    Entamoeba histolytica in culture produces a pentapeptide (MQCNS). This oligopeptide inhibits the in vitro and in vivo locomotion of human monocytes, hence its denomination Monocyte Locomotion Inhibitory Factor (MLIF). The original isolated peptide and its synthetic construct display similar effects, among others, being inhibition of the respiratory burst in monocytes and neutrophils, decrease of Dinitrochlorobenzene (DNCB) skin hypersensitivity in guinea pigs and gerbils, and delay of mononuclear leukocytes in human Rebuck skin windows with inhibition of vascular cell Very late antigen (VLA)-4 and Vascular adhesion molecules (VCAM) in endothelia and monocytes. The MLIF molecular mechanism of action is unknown, but data reveal its implication in Nuclear factor-kappa B (NF-κB) and Mitogenactivated protein kinase (MAPK) pathways. This could explain MLIF multiplicity of biological effects. On the other hand, the amebic peptide has been useful in treating experimental amebiasis of the liver. The amebic peptide is effective in reducing inflammation induced by carragenin and arthritis in a Collagen-induced arthritis (CIA) model. Microarray data from experimental arthritis revealed an MLIF gene expression profile that includes genes that are involved in apoptosis, cell adhesion, extracellular matrix, and inflammation / chemotaxis. MLIF could be involved in unsuspected biological factions because there is increasing data on the peptide effect on several cell activities. This review also presents uses of MLIF as described in patents.

  14. Hemocompatible poly(NIPAm-MBA-AMPS) colloidal nanoparticles as carriers of anti-inflammatory cell penetrating peptides.

    PubMed

    Bartlett, Rush L; Medow, Matthew R; Panitch, Alyssa; Seal, Brandon

    2012-04-09

    Anionic copolymer systems containing sulfated monomers have great potential for delivery of cationic therapeutics, but N-isopropylacrylamide (NIPAm) 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS) copolymer nanoparticles have seen limited characterization to date with regard to physical properties relevant to loading and release of therapeutics. Characterization of polymeric nanoparticles incorporating AMPS showed an increased size and decreased thermodynamic swelling ratios of AMPS containing particles as compared to NIPAm nanoparticles lacking AMPS. Particles with increasing AMPS addition showed an increased propensity for uniformity, intraparticle colloidal stability, and drug loading capacity. Peptide encapsulated in particles was shielded from peptide degradation in serum. Particles were shown not impede blood coagulation or to cause hemolysis. This study has demonstrated that AMPS incorporation into traditional NIPAm nanoparticles presents a tunable parameter for changing particle LCST, size, swelling ratio, ζ potential, and cationic peptide loading potential. This one-pot synthesis results in a thermosensitive anionic nanoparticle system that is a potentially useful platform to deliver cationic cell penetrating peptides.

  15. Highly localized divergence within supergenes in Atlantic cod (Gadus morhua) within the Gulf of Maine.

    PubMed

    Barney, Bryan T; Munkholm, Christiane; Walt, David R; Palumbi, Stephen R

    2017-03-31

    Atlantic cod (Gadus morhua), is known to vary genetically across the North Atlantic, Greenland, and Newfoundland. This genetic variation occurs both spatially and temporally through decades of heavy fishing, and is concentrated in three linkage disequilibrium blocks, previously defined by pedigreed linkage mapping analysis. Variation within these genomic regions is correlated with both seawater temperature and behavioral ecotype. The full extent and nature of these linkage groups is important information for interpreting cod genetic structure as a tool for future fisheries management. We conducted whole genome sequencing for 31 individual cod from three sub-populations in the Gulf of Maine. Across the genome, we found 3,390,654 intermediate to high frequency Single Nucleotide Polymorphisms (SNPs). We show that pairwise linkage analysis among these SNPs is a powerful tool to detect linkage disequilibrium clusters by recovering the three previously detected linkage groups and identifying the 1031 genes contained therein. Across these genes, we found significant population differentiation among spawning groups in the Gulf of Maine and between Georges Bank and Gulf of Maine. Coordinated divergence among these genes and their differentiation at both short and long spatial scales suggests that they are acting as linked supergenes in local adaptation of cod populations. Differentiation between SNPs in linkage disequilibrium blocks is the major signal of genetic differentiation between all groups tested within the Gulf of Maine. Our data provide a map of genes contained in these blocks, allowing an enhanced search for neutral genetic structure for demographic inference and fisheries modeling. Patterns of selection and the history of populations may be possible to identify in cod using this description of linkage disequilibrium blocks and future data sets to robustly separate neutral and selected genetic markers.

  16. Annexin 1 exerts anti-nociceptive effects after peripheral inflammatory pain through formyl-peptide-receptor-like 1 in rat dorsal root ganglion.

    PubMed

    Pei, L; Zhang, J; Zhao, F; Su, T; Wei, H; Tian, J; Li, M; Shi, J

    2011-12-01

    Annexin 1 (ANXA1) has analgesic effects in inflammatory pain. We aimed to investigate the anti-nociceptive role of ANXA1, at the dorsal root ganglion (DRG) level, through an interaction with formyl-peptide-receptor-like 1 (FPR2/ALX). Inflammatory pain was evoked by injecting complete Freund's adjuvant (CFA, 50 μl) into the hindpaw of male Sprague-Dawley rats. The distribution of ANXA1 and FPR2/ALX in L4/5 DRGs was evaluated by immunofluorescence. The expression of ANXA1 was measured by western blot. The involvement of FPR2/ALX in the anti-nociception of ANXA1 was investigated by thermal (irradiant heat) and mechanical (von Frey filament) pain tests with intrathecal (i.t.) ANXA1-derived peptide (Anxa1(2-26)), FPR2/ALX agonist 5(S)-6(R)-7-trihydroxyheptanoic-acid-methyl-ester (BML-111), and antagonist N-t-Boc-Phe-Leu-Phe-Leu-Phe (Boc1). ANXA1 and FPR2/ALX localized in the satellite glial cells and neurones in L4/5 DRGs. CFA treatment (n=20) increased ANXA1 expression in L4/5 DRGs within 7 days (P<0.01). I.T. Anxa1(2-26) (20 and 100 µg µl(-1)) and BML-111 (10 and 100 nmol) reduced CFA-induced thermal and mechanical nociception within 48 h (n=40) (P<0.05). However, i.t. Boc1 10 µg intensified inflammatory pain (P<0.05) and reversed the anti-nociceptive effect of Anxa1(2-26) (n=25) (P<0.05). Moreover, ANXA1 expression increased in L4/5 DRGs after i.t. Anxa1(2-26) (20 µg µl(-1)) (P<0.05) and BML-111 (10 nmol) (P<0.01) but decreased after i.t. Boc1 (10 and 100 µg) alone (P<0.01) or Boc1 (10 µg) co-injection with Anxa1(2-26) (20 µg µl(-1)) (P<0.05). Endogenous ANXA1 expression at the DRG level is involved in CFA-induced inflammatory pain, and i.t. ANXA1 20 µg µl(-1) produces its anti-nociceptive effect through FPR2/ALX.

  17. Anti-inflammatory effects of the nicotinergic peptides SLURP-1 and SLURP-2 on human intestinal epithelial cells and immunocytes.

    PubMed

    Chernyavsky, Alex I; Galitovskiy, Valentin; Shchepotin, Igor B; Grando, Sergei A

    2014-01-01

    A search for novel and more efficient therapeutic modalities of inflammatory bowel disease (IBD) is one of the most important tasks of contemporary medicine. The anti-inflammatory action of nicotine in IBD might be therapeutic, but its toxicity due to off-target and nonreceptor effects limited its use and prompted a search for nontoxic nicotinergic drugs. We tested the hypothesis that SLURP-1 and -2--the physiological nicotinergic substances produced by the human intestinal epithelial cells (IEC) and immunocytes--can mimic the anti-inflammatory effects of nicotine. We used human CCL-241 enterocytes, CCL-248 colonocytes, CCRF-CEM T-cells, and U937 macrophages. SLURP-1 diminished the TLR9-dependent secretion of IL-8 by CCL-241, and IFN γ-induced upregulation of ICAM-1 in both IEC types. rSLURP-2 inhibited IL-1 β-induced secretion of IL-6 and TLR4- and TLR9-dependent induction of CXCL10 and IL-8, respectively, in CCL-241. rSLURP-1 decreased production of TNFα by T-cells, downregulated IL-1 β and IL-6 secretion by macrophages, and moderately upregulated IL-10 production by both types of immunocytes. SLURP-2 downregulated TNFα and IFNγ R in T-cells and reduced IL-6 production by macrophages. Combining both SLURPs amplified their anti-inflammatory effects. Learning the pharmacology of SLURP-1 and -2 actions on enterocytes, colonocytes, T cells, and macrophages may help develop novel effective treatments of IBD.

  18. Argon release systematics of hypogene and supergene alunite based on progressive heating experiments from 100 to 1000°C

    NASA Astrophysics Data System (ADS)

    Itaya, Tetsumaru; Arribas, Antonio, Jr.; Okada, Toshinori

    1996-11-01

    Few minerals have as many different geological applications for Ksbnd Ar or 39Ar/ 40Ar dating as alunite (KAl 3(SO 4) 2(OH) 6), but a basic understanding of the systematics of argon release from this mineral is lacking. Progressive heating experiments from 100-1000°C at 100°C intervals were conducted in this study to obtain argon release patterns from hypogene and supergene alunite. The samples analyzed were selected from well understood deposits and are representative of the principal natural environments of acid-sulfate generation and related advanced argillic alteration and alunite formation. For gas extraction and purification, a low-blank metallic extraction-purification system used for dating silicates was complemented with a quartz-Pyrex glass line that included an external resistance furnace. The resulting patterns of argon release vs. temperature are well defined and similar for all the samples. Quantitative release of radiogenic 40Ar occurs during the dehydroxylation reaction of alunite at temperatures >400 and <700°C, in association with the first phase transformation of alunite during thermal decomposition to alum and alumina. This observation applies to alunites of different origin, regardless of characteristics such as grain size, crystal habit, growth temperature, and nature or origin of alunite-formation fluids. It applies as well to alunite treated chemically to remove small amounts of contaminant phases, such as illite. Argon released at <300°C is dominated by atmospheric argon adsorbed on the mineral surfaces, and Ar released at >800°C is mainly derived from the extraction system. The results indicate that the retentivity of Ar in fine-grained supergene alunite is similar to that of coarsely crystalline hypogene alunite. The data support the reliability of K-Ar dating of hypogene and supergene alunite and provide practical information to conduct routine high precision analyses.

  19. A Novel Combination of Wheat Peptides and Fucoidan Attenuates Ethanol-Induced Gastric Mucosal Damage through Anti-Oxidant, Anti-Inflammatory, and Pro-Survival Mechanisms.

    PubMed

    Kan, Juntao; Hood, Molly; Burns, Charlie; Scholten, Jeff; Chuang, Jennifer; Tian, Feng; Pan, Xingchang; Du, Jun; Gui, Min

    2017-09-06

    Gastritis or peptic ulcer is believed to affect about half of people worldwide. Traditional medications can lead to adverse effects, therefore, alternative nutritional strategies are needed to prevent the development of gastric mucosal damage. A novel combination of two food-grade ingredients, wheat peptides and fucoidan (WPF), was prepared to treat male Sprague Dawley rats for 30 days before gastric mucosal damage was induced by oral administration of ethanol. The serum levels of biomarkers were determined by enzyme-linked immunosorbent assay. Biomarkers in stomach tissue were analyzed using immunohistochemistry. In addition, human gastric epithelial cell line (GES-1) was used to investigate protein expression by Western blot. WPF could attenuate ethanol-induced gastric mucosal damage in an inverse dose-dependent manner, with both ulcer index and pathological index improved. WPF increased superoxide dismutase level and decreased malondialdehyde level. WPF also decreased the levels of interleukin-8, platelet-activating factor, and Caspase 3, while increasing the levels of prostaglandin E-2, epidermal growth factor (EGF), and EGF receptor (EGFR). Furthermore, phosphorylation of EGFR and extracellular signal-regulated kinases was induced by WPF in GES-1 cells. In conclusion, the novel combination of wheat peptides and fucoidan attenuated ethanol-induced gastric mucosal damage in rats through anti-oxidant, anti-inflammatory, and pro-survival mechanisms.

  20. Inhibition of CD4+ T lymphocyte binding to fibronectin and immune-cell accumulation in inflammatory sites by non-peptidic mimetics of Arg-Gly-Asp.

    PubMed Central

    Hershkoviz, R; Greenspoon, N; Mekori, Y A; Hadari, R; Alon, R; Kapustina, G; Lider, O

    1994-01-01

    The Arg-Gly-Asp (RGD) cell adhesion motif has been demonstrated in various studies to play a pivotal role in leucocyte and platelet interactions with plasma and extracellular matrix (ECM) glycoproteins. The recognition of the RGD sequence is mediated by heterodimeric receptors designated integrins of the beta 1 subfamily, expressed on distinct cell types, including T lymphocytes. We have recently shown that flexible non-peptidic mimetics of RGD, in which the two ionic side groups were separated by a linear spacer of 11 atoms, bound specifically to the platelet integrin alpha 11b beta 3, and inhibited T cell-mediated immune responses. The present study was designed to (i) further characterize the structural requirements for RGD interactions with CD4+ T cells, and (ii) examine the mechanisms by which the RGD mimetics interfere with immune cell reactivity in vivo. We now report that freezing the conformational degrees of freedom in the spacer chain, which fixes the relative orientation of the guanidinium and carboxylate side groups in a favourable manner, results in a higher level of inhibition of T cell binding to immobilized fibronectin, an RGD-containing ECM glycoprotein. In vivo, treatment of mice with relatively low doses of the RGD mimetics, but not the RGD peptide, inhibited the elicitation of an adoptively transferred DTH reaction. This inhibition was achieved by direct impairment of the ability of antigen-primed lymph node cells to migrate and accumulate in inflammatory sites. Hence, we suggest that the design and production of non-peptidic mimetics of RGD offers a novel approach to study defined parameters related to the structure-function requirements of small adhesion epitopes. Furthermore, this approach could be used therapeutically to inhibit pathological processes which depend on RGD recognition. PMID:7905794

  1. Monocytes and neutrophils from tuberculosis patients are insensitive to anti-inflammatory effects triggered by the prototypic formyl peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP)

    PubMed Central

    BEIGIER-BOMPADRE, M; ALEMÁN, M; BARRIONUEVO, P; FRANCO, M C; RUBEL, C J; SASIAIN, M Del C; PALERMO, M S; ABBATE, E; ISTURIZ, M A

    2003-01-01

    Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis where formyl peptides, which are cleavage products of bacterial and mitochondrial proteins, are present. In this study, we demonstrated that interferon gamma (IFN)-γ and interleukin (IL)-10 induced the overexpression of the receptor for the Fc portion of IgG I (FcγRI) in monocytes from tuberculosis (TB) patients, showing that these cells respond to IFN-γ and IL-10 signals. We also demonstrated that lower doses of IL-10 render monocytes from TB patients less responsive to higher doses of the cytokine. Although the prototypic formyl peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) is a well-known proinflammatory agonist, we have demonstrated previously that preincubation of monocytes with FMLP inhibited the up-regulation of FcγRI induced by IFN-γ or IL-10. This effect was not observed in monocytes from TB patientes. FMLP also induced the down-regulation of the expression of FcγRI in monocytes that had been activated already with IFN-γ. However, this effect of FMLP was not observed in monocytes from TB patients and supernatants from monocytes obtained from these patients were incapable of inducing the down-regulation of FcγRI. In contrast to normal donors, supernatants from FMLP-treated neutrophils from TB patients did not modify the basal level of expression of FcγRI in monocytes from normal donors. In conclusion, in this study we demonstrated the existence of two novel mechanisms that may contribute to the pathological effects generated by M. tuberculosis: the enhancement of FcγRI in response to IFN-γ and IL-10, and the unresponsiveness to the anti-inflammatory effects induced by formyl peptides. PMID:12869034

  2. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells

    PubMed Central

    Coffelt, Seth B.; Marini, Frank C.; Watson, Keri; Zwezdaryk, Kevin J.; Dembinski, Jennifer L.; LaMarca, Heather L.; Tomchuck, Suzanne L.; zu Bentrup, Kerstin Honer; Danka, Elizabeth S.; Henkle, Sarah L.; Scandurro, Aline B.

    2009-01-01

    Bone marrow-derived mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been shown to engraft into the stroma of several tumor types, where they contribute to tumor progression and metastasis. However, the chemotactic signals mediating MSC migration to tumors remain poorly understood. Previous studies have shown that LL-37 (leucine, leucine-37), the C-terminal peptide of human cationic antimicrobial protein 18, stimulates the migration of various cell types and is overexpressed in ovarian, breast, and lung cancers. Although there is evidence to support a pro-tumorigenic role for LL-37, the function of the peptide in tumors remains unclear. Here, we demonstrate that neutralization of LL-37 in vivo significantly reduces the engraftment of MSCs into ovarian tumor xenografts, resulting in inhibition of tumor growth as well as disruption of the fibrovascular network. Migration and invasion experiments conducted in vitro indicated that the LL-37-mediated migration of MSCs to tumors likely occurs through formyl peptide receptor like-1. To assess the response of MSCs to the LL-37-rich tumor microenvironment, conditioned medium from LL-37-treated MSCs was assessed and found to contain increased levels of several cytokines and pro-angiogenic factors compared with controls, including IL-1 receptor antagonist, IL-6, IL-10, CCL5, VEGF, and matrix metalloproteinase-2. Similarly, Matrigel mixed with LL-37, MSCs, or the combination of the two resulted in a significant number of vascular channels in nude mice. These data indicate that LL-37 facilitates ovarian tumor progression through recruitment of progenitor cell populations to serve as pro-angiogenic factor-expressing tumor stromal cells. PMID:19234121

  3. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells.

    PubMed

    Coffelt, Seth B; Marini, Frank C; Watson, Keri; Zwezdaryk, Kevin J; Dembinski, Jennifer L; LaMarca, Heather L; Tomchuck, Suzanne L; Honer zu Bentrup, Kerstin; Danka, Elizabeth S; Henkle, Sarah L; Scandurro, Aline B

    2009-03-10

    Bone marrow-derived mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been shown to engraft into the stroma of several tumor types, where they contribute to tumor progression and metastasis. However, the chemotactic signals mediating MSC migration to tumors remain poorly understood. Previous studies have shown that LL-37 (leucine, leucine-37), the C-terminal peptide of human cationic antimicrobial protein 18, stimulates the migration of various cell types and is overexpressed in ovarian, breast, and lung cancers. Although there is evidence to support a pro-tumorigenic role for LL-37, the function of the peptide in tumors remains unclear. Here, we demonstrate that neutralization of LL-37 in vivo significantly reduces the engraftment of MSCs into ovarian tumor xenografts, resulting in inhibition of tumor growth as well as disruption of the fibrovascular network. Migration and invasion experiments conducted in vitro indicated that the LL-37-mediated migration of MSCs to tumors likely occurs through formyl peptide receptor like-1. To assess the response of MSCs to the LL-37-rich tumor microenvironment, conditioned medium from LL-37-treated MSCs was assessed and found to contain increased levels of several cytokines and pro-angiogenic factors compared with controls, including IL-1 receptor antagonist, IL-6, IL-10, CCL5, VEGF, and matrix metalloproteinase-2. Similarly, Matrigel mixed with LL-37, MSCs, or the combination of the two resulted in a significant number of vascular channels in nude mice. These data indicate that LL-37 facilitates ovarian tumor progression through recruitment of progenitor cell populations to serve as pro-angiogenic factor-expressing tumor stromal cells.

  4. Oxidative weathering chemical migration under variably saturated conditions and supergene copper enrichment

    SciTech Connect

    Xu, Tianfu; Pruess, K.; Brimhall, G.

    1999-04-01

    Transport of oxygen gas from the land surface through an unsaturated zone has a strong influence on oxidative weathering processes. Oxidation of sulfide minerals such as pyrite (FeS{sub 2}), one of the most common naturally occurring minerals, is the primary source of acid drainage from mines and waste rock piles. Here we present a detailed numerical model of supergene copper enrichment that involves the oxidative weathering of pyrite (FeS{sub 2}) and chalcopyrite (CuFeS{sub 2}), and acidification that causes mobilization of metals in the unsaturated zone, with subsequent formation of enriched ore deposits of chalcocite (CuS) and covellite (Cu{sub 2}S) in the reducing conditions below the water table. We examine and identify some significant conceptual and computational issues regarding the oxidative weathering processes through the modeling tool. The dissolution of gaseous oxygen induced by the oxidation reduces oxygen partial pressure, as well as the total pressure of the gas phase. As a result, the gas flow is modified, then the liquid phase flow. Results indicate that this reaction effect on the fluid flow may not be important under ambient conditions, and gas diffusion can be a more important mechanism for oxygen supply than gas or liquid advection. Acidification, mobilization of metals, and alteration of primary minerals mostly take place in unsaturated zone (oxidizing), while precipitation of secondary minerals mainly occurs in saturated zone (reducing). The water table may be considered as an interface between oxidizing and reducing zones. Moving water table due to change of infiltration results in moving oxidizing zone and redistributing aqueous chemical constitutes and secondary mineral deposits. The oxidative weathering processes are difficult to model numerically, because concentrations of redox sensitive chemical species such as O{sub 2}(aq), SO{sub 4}{sup 2-} and HS{sup -} may change over tens of orders of magnitude between oxidizing and reducing

  5. Geochemical and biological characterisation of supergene efflorescences in pollymetallic mining wastes from Portman Bay (SE, Spain)

    NASA Astrophysics Data System (ADS)

    García-Lorenzo, Maria Luz; Herrero, Maria Jose; Martinez-Sanchez, Maria Jose; Molina-Ruiz, Jose; Hernandez, Carmen; Bech, Jaume; Perez-Sirvent, Carmen

    2017-04-01

    In freshly deposited sulphidic mine tailings, the pH is neutral or slightly alkaline. Due to pyrite oxidation, the pH decreases to values lower than 3 at which acidophilic iron- and sulphur-oxidizing prokaryotes prevail and accelerate the oxidation processes. Portman Bay is heavily polluted as a result of historical mining and processing activities, during which time great amounts of wastes were produced, characterised by a high potentially toxic elements (PTE) content, acidic pH and minerals resulting from supergene alteration. Three soil samples were collected from the most recent exploitation stage, stored in containers for a year and moistened simulating rainfall events. The percolates obtained were collected and naturally evaporated, obtaining three efflorescence samples. The existence of bacterial activity was evaluated by scanning electron microscopy (SEM). C15 sample is characterised by copiapite small crystals generating an homogeneous, porous mass. Inside the mass of copiapite crystals, both pyrite and gypsum were also found. In this sample, a laminae of material fills the pore space. The high carbon content shown in the spectrum of this material permits to characterise it as a biofilm. In the cross section sample of C15, a noticeable lamination of copiapite crystals has been observed, probably originated by dissolution processes. A clear limit between the lamination zone and the upper zone of the efflorescence was noticed, and here arborescent forms are developed. C17 and C18 also presented copiapite crystals, but, unlike C15, they do not present lamination and are characterized by an irregular shape and massive fabric. In C17, small crystals growing in the surface of this material were observed, generating small crusts. According to the spectrum analysis, these crusts are formed by alunogen. In C18, crystals of acicular morphology are present, and appear grouped at certain points. Therefore, out of the three natural efflorescences, biotic activity was

  6. Genesis of superimposed hypogene and supergene Fe orebodies in BIF at the Madoonga deposit, Yilgarn Craton, Western Australia

    NASA Astrophysics Data System (ADS)

    Duuring, Paul; Hagemann, Steffen

    2013-03-01

    The Madoonga iron ore body hosted by banded iron formation (BIF) in the Weld Range greenstone belt of Western Australia is a blend of four genetically and compositionally distinct types of high-grade (>55 wt% Fe) iron ore that includes: (1) hypogene magnetite-talc veins, (2) hypogene specular hematite-quartz veins, (3) supergene goethite-hematite, and (4) supergene-modified, goethite-hematite-rich detrital ores. The spatial coincidence of these different ore types is a major factor controlling the overall size of the Madoonga ore body, but results in a compositionally heterogeneous ore deposit. Hypogene magnetite-talc veins that are up to 3 m thick and 50 m long formed within mylonite and shear zones located along the limbs of isoclinal, recumbent F1 folds. Relative to least-altered BIF, the magnetite-talc veins are enriched in Fe2O3(total), P2O5, MgO, Sc, Ga, Al2O3, Cl, and Zr; and depleted in SiO2 and MnO2. Mafic igneous countryrocks located within 10 m of the northern contact of the mineralised BIF display the replacement of primary igneous amphibole and plagioclase, and metamorphic chlorite by hypogene ferroan chlorite, talc, and magnetite. Later-forming, hypogene specular hematite-quartz veins and their associated alteration halos partly replace magnetite-talc veins in BIF and formed during, to shortly after, the F2-folding and tilting of the Weld Range tectono-stratigraphy. Supergene goethite-hematite ore zones that are up to 150 m wide, 400 m long, and extend to depths of 300 m replace least-altered BIF and existing hypogene alteration zones. The supergene ore zones formed as a result of the circulation of surface oxidised fluids through late NNW- to NNE-trending, subvertical brittle faults. Flat-lying, supergene goethite-hematite-altered, detrital sediments are concentrated in a paleo-topographic depression along the southern side of the main ENE-trending ridge at Madoonga. Iron ore deposits of the Weld Range greenstone belt record remarkably similar

  7. Novel Nuclear Factor-KappaB Targeting Peptide Suppresses β-Amyloid Induced Inflammatory and Apoptotic Responses in Neuronal Cells.

    PubMed

    Srinivasan, Mythily; Bayon, Baindu; Chopra, Nipun; Lahiri, Debomoy K

    2016-01-01

    In the central nervous system (CNS), activation of the transcription factor nuclear factor-kappa B (NF-κβ) is associated with both neuronal survival and increased vulnerability to apoptosis. The mechanisms underlying these dichotomous effects are attributed to the composition of NF-κΒ dimers. In Alzheimer's disease (AD), β-amyloid (Aβ) and other aggregates upregulate activation of p65:p50 dimers in CNS cells and enhance transactivation of pathological mediators that cause neuroinflammation and neurodegeneration. Hence selective targeting of activated p65 is an attractive therapeutic strategy for AD. Here we report the design, structural and functional characterization of peptide analogs of a p65 interacting protein, the glucocorticoid induced leucine zipper (GILZ). By virtue of binding the transactivation domain of p65 exposed after release from the inhibitory IκΒ proteins in activated cells, the GILZ analogs can act as highly selective inhibitors of activated p65 with minimal potential for off-target effects.

  8. Amelioration of Cardiac Function and Activation of Anti-Inflammatory Vasoactive Peptides Expression in the Rat Myocardium by Low Level Laser Therapy

    PubMed Central

    Manchini, Martha Trindade; Serra, Andrey Jorge; Feliciano, Regiane dos Santos; Santana, Eduardo Tadeu; Antônio, Ednei Luis; de Tarso Camillo de Carvalho, Paulo; Montemor, Jairo; Crajoinas, Renato Oliveira; Girardi, Adriana Castello Costa; Tucci, Paulo José Ferreira; Silva, José Antônio

    2014-01-01

    Low-level laser therapy (LLLT) has been used as an anti-inflammatory treatment in several disease conditions, even when inflammation is a secondary consequence, such as in myocardial infarction (MI). However, the mechanism by which LLLT is able to protect the remaining myocardium remains unclear. The present study tested the hypothesis that LLLT reduces inflammation after acute MI in female rats and ameliorates cardiac function. The potential participation of the Renin-Angiotensin System (RAS) and Kallikrein-Kinin System (KKS) vasoactive peptides was also evaluated. LLLT treatment effectively reduced MI size, attenuated the systolic dysfunction after MI, and decreased the myocardial mRNA expression of interleukin-1 beta and interleukin-6 in comparison to the non-irradiated rat tissue. In addition, LLLT treatment increased protein and mRNA levels of the Mas receptor, the mRNA expression of kinin B2 receptors and the circulating levels of plasma kallikrein compared to non-treated post-MI rats. On the other hand, the kinin B1 receptor mRNA expression decreased after LLLT. No significant changes were found in the expression of vascular endothelial growth factor (VEGF) in the myocardial remote area between laser-irradiated and non-irradiated post-MI rats. Capillaries density also remained similar between these two experimental groups. The mRNA expression of the inducible nitric oxide synthase (iNOS) was increased three days after MI, however, this effect was blunted by LLLT. Moreover, endothelial NOS mRNA content increased after LLLT. Plasma nitric oxide metabolites (NOx) concentration was increased three days after MI in non-treated rats and increased even further by LLLT treatment. Our data suggest that LLLT diminishes the acute inflammation in the myocardium, reduces infarct size and attenuates left ventricle dysfunction post-MI and increases vasoactive peptides expression and nitric oxide (NO) generation. PMID:24991808

  9. A peptide inhibitor of C-jun N-terminal kinase modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation.

    PubMed

    Lehnert, Mark; Relja, Borna; Sun-Young Lee, Veronika; Schwestka, Birgit; Henrich, Dirk; Czerny, Christoph; Froh, Matthias; Borsello, Tiziana; Marzi, Ingo

    2008-08-01

    Hemorrhage and resuscitation (H/R) leads to phosphorylation of mitogen-activated stress kinases, an event that is associated with organ damage. Recently, a specific, cell-penetrating, protease-resistant inhibitory peptide of the mitogen-activated protein kinase c-JUN N-terminal kinase (JNK) was developed (D-JNKI-1). Here, using this peptide, we tested if inhibition of JNK protects against organ damage after H/R. Male Sprague-Dawley rats were treated with D-JNKI-1 (11 mg/kg, i.p.) or vehicle. Thirty minutes later, rats were hemorrhaged for 1 h to a MAP of 30 to 35 mmHg and then resuscitated with 60% of the shed blood and twice the shed blood volume as Ringer lactate. Tissues were harvested 2 h later. ANOVA with Tukey post hoc analysis or Kruskal-Wallis ANOVA on ranks, P < 0.05, was considered significant. c-JUN N-terminal kinase inhibition decreased serum alanine aminotransferase activity as a marker of liver injury by 70%, serum creatine kinase activity by 67%, and serum lactate dehydrogenase activity by 60% as compared with vehicle treatment. The histological tissue damage observed was blunted after D-JNKI-1 pretreatment both for necrotic and apoptotic cell death. Hepatic leukocyte infiltration and serum IL-6 levels were largely diminished after D-JNKI-1 pretreatment. The extent of oxidative stress as evaluated by immunohistochemical detection of 4-hydroxynonenal was largely abrogated after JNK inhibition. After JNK inhibition, activation of cJUN after H/R was also reduced. Hemorrhage and resuscitation induces a systemic inflammatory response and leads to end-organ damage. These changes are mediated, at least in part, by JNK. Therefore, JNK inhibition deserves further evaluation as a potential treatment option in patients after resuscitated blood loss.

  10. Persistency-field Eh-pH diagrams for sulfides and their application to supergene oxidation and enrichment of sulfide ore bodies

    USGS Publications Warehouse

    Sato, M.

    1992-01-01

    At temperatures prevailing near the Earth's surface, metastable co-existence of chemical substances is common because chemical reactions that would directly lead to the attainment of thermody-namically most stable equilibria are often blocked by high activation energy barriers. The persistency of a metastable assemblage is then governed by alternative reaction paths that provide lower activation energy barriers. Comparison of observed mineral assemblages in the supergene oxidized and enriched sulfide ores with corresponding stability Eh-pH diagrams reveals that the supergene assemblages are mostly metastable due primarily to the persistency of sulfide minerals beyond stability boundaries. A new set of diagrams called persistency-field Eh-pH diagrams has been constructed for binary metal sulfides on the basis of electrochemical and other experimental data. Each diagram delineates the persistency field, which is a combined field of thermodynamic stability and reaction path-controlled metastability, for a specific sulfide mineral. When applied to the supergene assemblages, these new diagrams show much better correspondence to the field observations. Although there may still be room for further refinement, the new diagrams appear to provide a strong visual aid to the understanding of the behavior of sulfide minerals in the supergene conditions. ?? 1992.

  11. Novel Nuclear Factor-KappaB Targeting Peptide Suppresses β-Amyloid Induced Inflammatory and Apoptotic Responses in Neuronal Cells

    PubMed Central

    Srinivasan, Mythily; Bayon, Baindu; Chopra, Nipun; Lahiri, Debomoy K.

    2016-01-01

    In the central nervous system (CNS), activation of the transcription factor nuclear factor-kappa B (NF-κβ) is associated with both neuronal survival and increased vulnerability to apoptosis. The mechanisms underlying these dichotomous effects are attributed to the composition of NF-κΒ dimers. In Alzheimer’s disease (AD), β-amyloid (Aβ) and other aggregates upregulate activation of p65:p50 dimers in CNS cells and enhance transactivation of pathological mediators that cause neuroinflammation and neurodegeneration. Hence selective targeting of activated p65 is an attractive therapeutic strategy for AD. Here we report the design, structural and functional characterization of peptide analogs of a p65 interacting protein, the glucocorticoid induced leucine zipper (GILZ). By virtue of binding the transactivation domain of p65 exposed after release from the inhibitory IκΒ proteins in activated cells, the GILZ analogs can act as highly selective inhibitors of activated p65 with minimal potential for off-target effects. PMID:27764084

  12. Mapping the Interaction of B Cell Leukemia 3 (BCL-3) and Nuclear Factor κB (NF-κB) p50 Identifies a BCL-3-mimetic Anti-inflammatory Peptide*

    PubMed Central

    Collins, Patricia E.; Grassia, Gianluca; Colleran, Amy; Kiely, Patrick A.; Ialenti, Armando; Maffia, Pasquale; Carmody, Ruaidhrí J.

    2015-01-01

    The NF-κB transcriptional response is tightly regulated by a number of processes including the phosphorylation, ubiquitination, and subsequent proteasomal degradation of NF-κB subunits. The IκB family protein BCL-3 stabilizes a NF-κB p50 homodimer·DNA complex through inhibition of p50 ubiquitination. This complex inhibits the binding of the transcriptionally active NF-κB subunits p65 and c-Rel on the promoters of NF-κB target genes and functions to suppress inflammatory gene expression. We have previously shown that the direct interaction between p50 and BCL-3 is required for BCL-3-mediated inhibition of pro-inflammatory gene expression. In this study we have used immobilized peptide array technology to define regions of BCl-3 that mediate interaction with p50 homodimers. Our data show that BCL-3 makes extensive contacts with p50 homodimers and in particular with ankyrin repeats (ANK) 1, 6, and 7, and the N-terminal region of Bcl-3. Using these data we have designed a BCL-3 mimetic peptide based on a region of the ANK1 of BCL-3 that interacts with p50 and shares low sequence similarity with other IκB proteins. When fused to a cargo carrying peptide sequence this BCL-3-derived peptide, but not a mutated peptide, inhibited Toll-like receptor-induced cytokine expression in vitro. The BCL-3 mimetic peptide was also effective in preventing inflammation in vivo in the carrageenan-induced paw edema mouse model. This study demonstrates that therapeutic strategies aimed at mimicking the functional activity of BCL-3 may be effective in the treatment of inflammatory disease. PMID:25922067

  13. Calcitonin gene-related peptide modulates the production of pro-inflammatory cytokines associated with periprosthetic osteolysis by THP-1 macrophage-like cells.

    PubMed

    Jablonski, Heidrun; Kauther, Max Daniel; Bachmann, Hagen Sjard; Jäger, Marcus; Wedemeyer, Christian

    2015-01-01

    An anti-resorptive impact of the neuropeptide calcitonin gene-related peptide (CGRP) on periprosthetic osteolysis, the leading cause of early prosthesis loosening, has been shown previously. In this study, the impact of CGRP on pro-inflammatory cytokine production associated with periprosthetic osteolysis was analysed using THP-1 macrophage-like cells. Cells were stimulated with ultra-high-molecular-weight polyethylene (UHMWPE) particles (cell-to-particle ratios of 1:100 and 1:500) and lipopolysaccharides (LPS; 1 µg/ml) to establish osteolytic conditions, and simultaneously treated with CGRP (10(-8)M). Receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL) and tumour necrosis factor (TNF)-α mRNA expression were measured by quantitative RT-PCR. RANK protein was detected by Western blot. Secreted protein levels of TNF-α as well as interleukin (IL)-1β and IL-6 were quantified in cell culture supernatants by ELISA and Bio-Plex cytokine assay, respectively. Activation of macrophage-like cells failed to enhance the production of RANK but led to a dose- and time-dependent increase of TNF-α mRNA and secreted protein levels of TNF-α, IL-1β and IL-6. Application of CGRP time-dependently suppressed TNF-α mRNA expression induced by low-particle concentrations and LPS, while both particle- and LPS-induced secretion of TNF-α was inhibited. A pronounced inhibitory effect of CGRP on LPS-induced cytokine production at 24 h of incubation was also observed with IL-1β and IL-6. CGRP shows a time-dependent inhibitory effect on the secretion of osteolysis-associated pro-inflammatory cytokines, indicating an indirect anti-resorptive influence of the neuropeptide on both aseptic prosthesis loosening and bacterially induced bone resorption which might enhance the life time of total joint replacements. © 2014 S. Karger AG, Basel.

  14. Differential induction of innate defense antimicrobial peptides in primary nasal epithelial cells upon stimulation with inflammatory cytokines, Th17 cytokines or bacterial conditioned medium from Staphylococcus aureus isolates.

    PubMed

    Burgey, Christine; Kern, Winfried V; Römer, Winfried; Rieg, Siegbert

    2016-01-01

    To date it is incompletely understood why half of the human population is intrinsically resistant to Staphylococcus aureus colonization whereas the other half is intermittently or permanently colonized. Nasal colonization represents the primary niche for S. aureus. We therefore investigated whether primary nasal epithelial cells (HNEC) express antimicrobial peptides (AMPs) upon stimulation by inflammatory cytokines or bacterial conditioned medium (BCM) of different colonizing and invasive staphylococci. Stimulation with classical cytokines (IL-1β, TNF-α, IFN-γ) potently induced hBD-3 and RNase7 in HNEC. Th17 cytokines (IL-17A, IL-17F, IL-22) yielded comparably weak hBD-3 and RNase7 induction and no synergistic effects with classical cytokines. BCM of S. aureus and Staphylococcus epidermidis isolates moderately induced hBD3 and RNase7 mRNA expression without significant differences when comparing colonizing vs. invasive isolates. Our results indicate that HNEC contribute to the innate defense by secretion of an AMP-containing chemical defense shield along the nasal mucosa i.e. within the primary colonization niche of S. aureus. Further studies are needed to investigate whether a deficient AMP expression in the nasal mucosa may be related to different S. aureus carrier states. AMPs or AMP-inducing agents may be promising candidates for future topical decolonization regimens that aim to prevent invasive S. aureus infections.

  15. The Bi'r Tawilah deposit, central western Saudi Arabia: Supergene enrichment of a Pan-African epithermal gold mineralization

    NASA Astrophysics Data System (ADS)

    Surour, Adel A.; Harbi, Hesham M.; Ahmed, Ahmed H.

    2014-01-01

    The Bi'r Tawilah gold deposit in central western Saudi Arabia represents a Pan-African example of gold mineralization in which both hypogene and supergene ores are recorded. The sulphidic gold ore is hosted in intermediate to felsic intrusions that occur along the N-S trending thrust-fault zone within the so-called “Nabitah orogenic zone”. There are four rock units present (from oldest to youngest): serpentinites and related listwaenites, diorites, granitic rocks and porphyries. Hydrothermal alteration consists of chloritization, sericitization, carbonatization and silicification and affects all rock types. Chloritization of biotite results in abundant rutile, whereas sulphidization coincides with carbonatization. The Bi'r Tawilah ore is confined to NW-trending shears (Riedel fractures) related to N-S slip of the pre-existing Tawilah thrust due to activation within the Najd fault system. Samples from the boreholes show macro- and microscopic evidence of shearing such as micro-shear planes and strain shadows of pyrite. Sulphides and gold are present in most rock types. Paragenetically, the sulphides consist of abundant pyrite and relatively lesser amounts of arsenopyrite, in addition to very minor chalcopyrite, sphalerite and galena. In all boreholes, it was noticed that the abundance of arsenopyrite increases with depth. The elevated silver content of electrum (∼13-22 wt%) at Bi'r Tawilah is typical of gold deposits and low-sulphidation epithermal deposits. The early mineralization stage took place in proximity to hydrothermally altered intermediate to felsic intrusions. The aerially restricted hydrothermal alteration by carbon-aqueous fluids led to ore remobilization in which gold amounts up to 4.3 g/t. Finally, gold enrichment (up to 5.4 g/t) resulted from supergene alteration that took place during weathering above the water table at a depth of ∼20-25 m.

  16. Effects of Spinally Administered Bifunctional Nociceptin/Orphanin FQ Peptide Receptor/μ-Opioid Receptor Ligands in Mouse Models of Neuropathic and Inflammatory Pain

    PubMed Central

    Sukhtankar, Devki D.; Zaveri, Nurulain T.; Husbands, Stephen M.

    2013-01-01

    Nociceptin/orphanin FQ peptide receptor (NOP) agonists produce antinociceptive effects in animal models after spinal administration and potentiate μ-opioid receptor (MOP)-mediated antinociception. This study determined the antinociceptive effects of spinally administered bifunctional NOP/MOP ligands and the antinociceptive functions of spinal NOP and MOP receptors in mice. Antinociceptive effects of bifunctional NOP/MOP ligands BU08028 [(2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol] and SR16435 [1-(1-(2,3,3α,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin-2-one] were pharmacologically compared with the putative bifunctional ligand buprenorphine, selective NOP agonist SCH221510 [3-endo-8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol] and selective MOP agonist morphine in neuropathic and inflammatory pain models. Additionally, the degree of tolerance development to the antiallodynic effects of SR16435 and buprenorphine were determined after repeated intrathecal administration. Our data indicated that BU08028 and SR16435 were more potent than morphine and SCH221510 in attenuating nerve injury-induced tactile allodynia and inflammation-induced thermal hyperalgesia. Coadministration of receptor-selective antagonists further revealed that both NOP and MOP in the spinal cord mediated the antiallodynic effects of BU08028 and SR16435, but intrathecal buprenorphine-induced antiallodynic effects were primarily mediated by MOP. Repeated intrathecal administration of SR16435 resulted in reduced and slower development of tolerance to its antiallodynic effects compared with buprenorphine. In conclusion, both NOP and MOP receptors in the spinal cord independently drive antinociception in mice. Spinally administered bifunctional NOP/MOP ligands not only can effectively attenuate neuropathic and inflammatory pain, but also have higher antinociceptive potency with reduced

  17. Potentiation of evoked calcitonin gene-related peptide release from oral mucosa: a potential basis for the pro-inflammatory effects of nicotine

    PubMed Central

    Dussor, Gregory O.; Leong, Anthony S.; Gracia, Nicholas B.; Kilo, Sonja; Price, Theodore J.; Hargreaves, Kenneth M.; Flores, Christopher M.

    2010-01-01

    Inflammation of the buccal mucosa, gingiva and periodontal tissues is a significant problem in users of nicotine-containing tobacco products; however, the potential role of nicotine in the development of this inflammation is unclear. In many tissues, nicotine, acting through nicotinic acetylcholine receptors (nAChRs), has been shown to increase the release of the pro-inflammatory mediator calcitonin gene-related peptide (CGRP) thereby potentially contributing to neurogenic inflammation. The purpose of the present studies was to determine the effects of nicotine and other nAChR agonists on capsaicin-evoked immunoreactive CGRP (iCGRP) release from rat buccal mucosa and to identify a potential cellular basis for these effects. Using a previously validated model of in vitro superfusion, we show that the nAChR agonists nicotine (EC50 557 μM), epibatidine (EC50 317 pM) and cytisine (EC50 4.83 nM) potentiated capsaicin-evoked iCGRP release in a concentration-dependent manner by 123, 70 and 76%, respectively. The expression and distribution patterns of the mRNA transcripts encoding the α3, α4 and α6 nAChR subunits and their colocalization with CGRP and the capsaicin receptor VR1 were examined in rat trigeminal ganglion using combined in situ hybridization and immunohistofluorescence. Of all trigeminal neurons counted, mRNA encoding the α3, α4 and α6 subunits was found, respectively, in 14.45, 9.2 and 19.21% of neurons. The cell body diameter of most neurons containing any nAChR subunit was in the 30–40 μm range with slightly fewer in the 20–30 μm range. Co-localization of these α subunit transcripts with either CGRP or VR1 immunoreactivity ranged from approximately 5 to 7% for α4 and over 8% for α3 to 18% for α6. These data support the hypothesis that nicotinic agents, acting at nAChRs contained on primary sensory neurons, are capable of directly modulating the stimulated release of iCGRP In the case of users of nicotine-containing tobacco products, this

  18. N-terminal pro-brain-type natriuretic peptide (NT-pro-BNP) and mortality risk in early inflammatory polyarthritis: results from the Norfolk Arthritis Registry (NOAR)

    PubMed Central

    Mirjafari, Hoda; Welsh, Paul; Verstappen, Suzanne M M; Wilson, Paddy; Marshall, Tarnya; Edlin, Helena; Bunn, Diane; Chipping, Jacqueline; Lunt, Mark; Symmons, Deborah P M; Sattar, Naveed; Bruce, Ian N

    2014-01-01

    Background We measured N-terminal pro-brain natriuretic peptide (NT-pro-BNP), a marker of cardiac dysfunction, in an inception cohort with early inflammatory polyarthritis (IP) and assessed its association with disease phenotype, cardiovascular disease (CVD), all-cause and CVD related mortality. Methods Subjects with early IP were recruited to the Norfolk Arthritis Register from January 2000 to December 2008 and followed up to death or until March 2010 including any data from the national death register. The associations of baseline NT-pro-BNP with IP related factors and CVD were assessed by linear regression. Cox proportional hazards models examined the independent association of baseline NT-pro-BNP with all-cause and CVD mortality. Results We studied 960 early IP subjects; 163 (17%) had prior CVD. 373 (39%) patients had a baseline NT-pro-BNP levels ≥100 pg/ml. NT-pro-BNP was associated with age, female gender, HAQ score, CRP, current smoking, history of hypertension, prior CVD and the presence of carotid plaque. 92 (10%) IP subjects died including 31 (3%) from CVD. In an age and gender adjusted analysis, having a raised NT-pro-BNP level (≥100 pg/ml) was associated with both all-cause and CVD mortality (adjusted HR (95% CI) 2.36 (1.42 to 3.94) and 3.40 (1.28 to 9.03), respectively). These findings were robust to adjustment for conventional CVD risk factors and prevalent CVD. Conclusions In early IP patients, elevated NT-pro-BNP is related to HAQ and CRP and predicts all-cause and CVD mortality independently of conventional CVD risk factors. Further study is required to identify whether NT-pro-BNP may be clinically useful in targeting intensive interventions to IP patients at greatest risk of CVD. PMID:23511225

  19. Extreme 34S depletions in ZnS at the Mike gold deposit, Carlin Trend, Nevada: Evidence for bacteriogenic supergene sphalerite

    USGS Publications Warehouse

    Bawden, T.M.; Einaudi, M.T.; Bostick, B.C.; Meibom, A.; Wooden, J.; Norby, J.W.; Orobona, M.J.T.; Chamberlain, C.P.

    2003-01-01

    We identified submicrometer-sized framboidal sphalerite (ZnS) below the base of supergene oxidation in a Carlin-type gold deposit of Eocene age in Nevada, United States, where the framboidal sphalerite forms a blanket-like body containing >400,000 metric tons of zinc. Framboidal sphalerite <0.1 ??m in diameter, formed in the early Miocene, ranges from <0.1 to 0.35 mol% FeS; the ??34S values range from -25??? to -70???, the lowest values measured in a marine or terrestrial environment. These S isotope data demonstrate the involvement of sulfate-reducing bacteria and provide the first documentation that sphalerite can form significant supergene sulfide-enrichment blankets.

  20. Acid activation of Trpv1 leads to an up-regulation of calcitonin gene-related peptide expression in dorsal root ganglion neurons via the CaMK-CREB cascade: a potential mechanism of inflammatory pain.

    PubMed

    Nakanishi, Masako; Hata, Kenji; Nagayama, Tomotaka; Sakurai, Teruhisa; Nishisho, Toshihiko; Wakabayashi, Hiroki; Hiraga, Toru; Ebisu, Shigeyuki; Yoneda, Toshiyuki

    2010-08-01

    Increased production of calcitonin gene-related peptide (CGRP) in sensory neurons is implicated in inflammatory pain. The inflammatory site is acidic due to proton release from infiltrating inflammatory cells. Acid activation of peripheral nociceptors relays pain signals to the CNS. Here, we examined whether acid activated the transient receptor potential vanilloid subtype 1 (Trpv1), a widely recognized acid-sensing nociceptor and subsequently increased CGRP expression. Chemically induced inflammation was associated with thermal hyperalgesia and increased CGRP expression in dorsal root ganglion (DRG) in rats. In organ cultures of DRG, acid (pH 5.5) elevated CGRP expression and the selective Trpv1 antagonist 5'-Iodoresiniferatoxin decreased it. Trpv1-deficient DRG showed reduced CGRP increase by acid. Of note, many of CGRP/Trpv1-positive DRG neurons exhibited the phosphorylation of cAMP response element-binding protein (CREB), a nociceptive transcription factor. Knockdown of CREB by small interfering RNA or a dominant-negative form of CREB diminished acid-elevated CGRP expression. Acid elevated the transcriptional activity of CREB, which in turn stimulated CGRP gene promoter activity. These effects were inhibited by a Ca(2+)/calmodulin-dependent protein kinase (CaMK) inhibitor KN-93. In conclusion, our results suggest that inflammatory acidic environments activate Trpv1, leading to an up-regulation of CGRP expression via CaMK-CREB cascade, a series of events that may be associated with inflammatory pain.

  1. Physical Activity in Older Men: Longitudinal Associations with Inflammatory and Hemostatic Biomarkers, N-Terminal Pro-Brain Natriuretic Peptide, and Onset of Coronary Heart Disease and Mortality

    PubMed Central

    Jefferis, Barbara J; Whincup, Peter H; Lennon, Lucy T; Papacosta, Olia; Goya Wannamethee, S

    2014-01-01

    Objectives To examine associations between habitual physical activity (PA) and changes in PA and onset of coronary heart disease (CHD) and the pathways linking PA to CHD. Design British Regional Heart Study population-based cohort; men completed questionnaires in 1996 and 1998 to 2000, attended rescreen in 1998 to 2000, and were followed up to June 2010. Setting Community. Participants Of 4,252 men recruited from primary care centers (77% of those invited and eligible) who were rescreened in 1998 to 2000, 3,320 were ambulatory and free from CHD, stroke, and heart failure and participated in the current study. Measurements Usual PA (regular walking and cycling, recreational activity and sport). Outcome was first fatal or nonfatal myocardial infarction. Results In 3,320 ambulatory men, 303 first and 184 fatal CHD events occurred during a median of 11 years of follow-up; 9% reported no usual PA, 23% occasional PA, and 68% light or more-intense PA. PA was inversely associated with novel risk markers C-reactive protein, D-dimer, von Willebrand Factor and N-terminal pro-brain natriuretic peptide (NT-proBNP). Compared with no usual PA, hazard ratios (HRs) for CHD events, adjusted for age and region, were 0.52 (95% confidence interval (CI) = 0.34–0.79) for occasional PA, 0.47 (95% CI = 0.30–0.74) for light PA, 0.51 (95% CI = 0.32–0.82) for moderate PA, and 0.44 (95% CI = 0.29–0.65) for moderately vigorous or vigorous PA (P for linear trend = .004). Adjustment for established and novel risk markers somewhat attenuated HRs and abolished linear trends. Compared with men who remained inactive, men who maintained at least light PA had an HR for CHD events of 0.73 (95% CI = 0.53–1.02) and men whose PA level increased had an HR of 0.86 (95% CI = 0.55–1.35). Conclusion Even light PA was associated with significantly lower risk of CHD events in healthy older men, partly through inflammatory and hemostatic mechanisms and cardiac function (NT-proBNP). PMID

  2. Physical activity in older men: longitudinal associations with inflammatory and hemostatic biomarkers, N-terminal pro-brain natriuretic peptide, and onset of coronary heart disease and mortality.

    PubMed

    Jefferis, Barbara J; Whincup, Peter H; Lennon, Lucy T; Papacosta, Olia; Goya Wannamethee, S

    2014-04-01

    To examine associations between habitual physical activity (PA) and changes in PA and onset of coronary heart disease (CHD) and the pathways linking PA to CHD. British Regional Heart Study population-based cohort; men completed questionnaires in 1996 and 1998 to 2000, attended rescreen in 1998 to 2000, and were followed up to June 2010. Community. Of 4,252 men recruited from primary care centers (77% of those invited and eligible) who were rescreened in 1998 to 2000, 3,320 were ambulatory and free from CHD, stroke, and heart failure and participated in the current study. Usual PA (regular walking and cycling, recreational activity and sport). Outcome was first fatal or nonfatal myocardial infarction. In 3,320 ambulatory men, 303 first and 184 fatal CHD events occurred during a median of 11 years of follow-up; 9% reported no usual PA, 23% occasional PA, and 68% light or more-intense PA. PA was inversely associated with novel risk markers C-reactive protein, D-dimer, von Willebrand Factor and N-terminal pro-brain natriuretic peptide (NT-proBNP). Compared with no usual PA, hazard ratios (HRs) for CHD events, adjusted for age and region, were 0.52 (95% confidence interval (CI) = 0.34-0.79) for occasional PA, 0.47 (95% CI = 0.30-0.74) for light PA, 0.51 (95% CI = 0.32-0.82) for moderate PA, and 0.44 (95% CI = 0.29-0.65) for moderately vigorous or vigorous PA (P for linear trend = .004). Adjustment for established and novel risk markers somewhat attenuated HRs and abolished linear trends. Compared with men who remained inactive, men who maintained at least light PA had an HR for CHD events of 0.73 (95% CI = 0.53-1.02) and men whose PA level increased had an HR of 0.86 (95% CI = 0.55-1.35). Even light PA was associated with significantly lower risk of CHD events in healthy older men, partly through inflammatory and hemostatic mechanisms and cardiac function (NT-proBNP). © 2014, Copyright the Authors. Journal compilation © 2014, The American Geriatrics Society.

  3. Hemoglobin and B-type natriuretic peptide preoperative values but not inflammatory markers, are associated with postoperative morbidity in cardiac surgery: a prospective cohort analytic study

    PubMed Central

    2013-01-01

    Introduction Risk stratification in cardiac surgery significantly impacts outcome. This study seeks to define whether there is an independent association between the preoperative serum level of hemoglobin (Hb), leukocyte count (LEUCO), high sensitivity C-reactive protein (hsCRP), or B-type natriuretic peptide (BNP) and postoperative morbidity and mortality in cardiac surgery. Methods Prospective, analytic cohort study, with 554 adult patients undergoing cardiac surgery in a tertiary cardiovascular hospital and followed up for 12 months. The cohort was distributed according to preoperative values of Hb, LEUCO, hsCRP, and BNP in independent quintiles for each of these variables. Results After adjustment for all covariates, a significant association was found between elevated preoperative BNP and the occurrence of low postoperative cardiac output (OR 3.46, 95% CI 1.53–7.80, p = 0.003) or postoperative atrial fibrillation (OR 3.8, 95% CI 1.45–10.38). For the combined outcome (death/acute coronary syndrome/rehospitalization within 12 months), we observed an OR of 1.93 (95% CI 1.00–3.74). An interaction was found between BNP level and the presence or absence of diabetes mellitus. The OR for non-diabetics was 1.26 (95% CI 0.61–2.60) and for diabetics was 18.82 (95% CI 16.2–20.5). Preoperative Hb was also significantly and independently associated with the occurrence of postoperative low cardiac output (OR 0.33, 95% CI 0.13–0.81, p = 0.016). Both Hb and BNP were significantly associated with the lengths of intensive care unit and hospital stays and the number of transfused red blood cells (p < 0.002). Inflammatory markers, although associated with adverse outcomes, lost statistical significance when adjusted for covariates. Conclusions High preoperative BNP or low Hb shows an association of independent risk with postoperative outcomes, and their measurement could help to stratify surgical risk. The ability to predict the onset of atrial fibrillation or

  4. Distribution and assessment of Pb in the supergene environment of the Huainan Coal Mining Area, Anhui, China.

    PubMed

    Fang, Ting; Liu, Guijian; Zhou, Chuncai; Yuan, Zijiao; Lam, Paul Kwan Sing

    2014-08-01

    Coal mining area is highly subject to lead (Pb) pollution from coal mining activities. Several decades of coal mining and processing practices in dozens of coal mines in the Huainan Coal Mining Area (HCMA) have led to the accumulation of massive amounts of coal gangue, which piled in dumps. In order to investigate the impacts of coal gangue dumps on Pb level in the supergene media of the HCMA, a systematic sampling campaign comprising coal gangue, soil, wheat, and earthworm samples was conducted. The average Pb content in the coal mining area soil is 24 mg/kg, which is slightly higher than the associated coal gangues (23 mg/kg) and markedly higher than reference region soil (12.6 mg/kg). Soil in the HCMA present a slight to moderate Pb contamination, which might be related to the weathering and leaching of coal gangue dumps. Lateral distribution of Pb in HCMA soil differed among individual coal mines. The soil profile distribution of Pb depends on both natural and anthropogenic contributions. Average Pb content is higher in roots than in stems, leaves, and wheat husks, while the Pb level in seeds exceeded the maximum Pb allowance for foods (Maximum Levels of Contaminants in Foods of China, GB 2762-2012). Earthworms in the selected area are significantly enriched in Pb, suggesting higher bio-available Pb level in soil in the HCMA.

  5. Mineralogical and geochemical characterization of supergene Cu-Pb-Zn-V ores in the Oriental High Atlas, Morocco

    NASA Astrophysics Data System (ADS)

    Verhaert, Michèle; Bernard, Alain; Dekoninck, Augustin; Lafforgue, Ludovic; Saddiqi, Omar; Yans, Johan

    2017-07-01

    In the Moroccan High Atlas, two sulfide deposits hosted by Jurassic dolostones underwent significant weathering. In the Cu deposit of Jbel Klakh, several stages of supergene mineralization are distinguished: (1) the replacement of hypogene sulfides in the protolith (chalcopyrite) by secondary sulfides in the cementation zone (bornite, digenite, chalcocite, covellite), (2) the formation of oxidized minerals in the saprolite (malachite, azurite, brochantite) where the environment becomes more oxidizing and neutral, and (3) the precipitation of late carbonates (calcite) and iron (hydr-)oxides in the laterite. The precipitation of carbonates is related to the dissolution of dolomitic host rocks, which buffers the fluid acidity due to the oxidation of sulfides. In the Jbel Haouanit Pb-Zn deposit, the mineral assemblage is dominated by typical calamine minerals, Cu minerals (chalcocite, covellite, malachite), and a Cu-Pb-Zn vanadate (mottramite). Galena is successively weathered in anglesite and cerussite. Sphalerite is weathered in smithsonite, which is rapidly replaced by hydrozincite. Late iron (hydr-)oxides are mainly found at the top of both deposits (laterite). Both deposits are thus characterized by specific mineral zoning, from laterite to protolith, related to variations in the mineralogy and ore grades and probably caused by varying Eh-pH conditions.

  6. A CCL chemokine-derived peptide (CDIP-2) exerts anti-inflammatory activity via CCR1, CCR2 and CCR3 chemokine receptors: Implications as a potential therapeutic treatment of asthma.

    PubMed

    Méndez-Enríquez, E; Medina-Tamayo, J; Soldevila, G; Fortoul, T I; Anton, B; Flores-Romo, L; García-Zepeda, E A

    2014-05-01

    Allergic asthma is a chronic inflammatory disease characterized by the accumulation of eosinophils, Th2 cells and mononuclear cells in the airways, leading to changes in lung architecture and subsequently reduced respiratory function. We have previously demonstrated that CDIP-2, a chemokine derived peptide, reduced in vitro chemotaxis and decreased cellular infiltration in a murine model of allergic airway inflammation. However, the mechanisms involved in this process have not been identified yet. Now, we found that CDIP-2 reduces chemokine-mediated functions via interactions with CCR1, CCR2 and CCR3. Moreover, using bone marrow-derived eosinophils, we demonstrated that CDIP-2 modifies the calcium fluxes induced by CCL11 and down-modulated CCR3 expression. Finally, CDIP-2 treatment in a murine model of OVA-induced allergic airway inflammation reduced leukocyte recruitment and decreases production of cytokines. These data suggest that chemokine-derived peptides represent new therapeutic tools to generate more effective antiinflammatory drugs.

  7. Single Intramammary Infusion of Recombinant Bovine Interleukin-8 at Dry-Off Induces the Prolonged Secretion of Leukocyte Elastase, Inflammatory Lactoferrin-Derived Peptides, and Interleukin-8 in Dairy Cows

    PubMed Central

    Watanabe, Atsushi; Hirota, Jiro; Shimizu, Shinya; Inumaru, Shigeki; Kimura, Kazuhiro

    2012-01-01

    A single intramammary infusion of recombinant bovine interleukin-8 (IL-8) at 50 μg/quarter/head, but not 10 μg/quarter/head, induced clinical mastitis in three of four cows during the dry-off period, resulting in an elevated rectal temperature, redness and swelling of the mammary gland, extensive polymorphonuclear leukocyte (PMNL) infiltration, and milk clot formation from 1 to 28 days post infusion (PI). In the mammary secretions of the mastitic glands, high levels of IL-8 were sustained from 8 hours to 28 days PI, peaking at 1–3 days PI. The levels of leukocyte-derived elastase and inflammatory 22 and 23 kDa lactoferrin derived peptides (LDP) were also increased in the mammary secretions from the mastitic glands. In addition to the experimentally induced mastitis, the mammary secretions from the glands of cattle with spontaneous Staphylococcus aureus dry-period mastitis displayed milk clot formations and significant increases in their levels of PMNL counts, elastase, LDP, and IL-8, compared with those of the mammary secretions from the uninfected glands. These results suggest that after an intramammary infusion of IL-8 has elicited inflammatory responses, it induces the prolonged secretion of elastase, inflammatory LDP, and IL-8, and that long-lasting IL-8-induced inflammatory reactions are involved in the pathogenesis of S. aureus dry-period mastitis. PMID:22919545

  8. Supergene destruction of a hydrothermal replacement alunite deposit at Big Rock Candy Mountain, Utah: Mineralogy, spectroscopic remote sensing, stable-isotope, and argon-age evidences

    USGS Publications Warehouse

    Cunningham, C.G.; Rye, R.O.; Rockwell, B.W.; Kunk, M.J.; Councell, T.B.

    2005-01-01

    Big Rock Candy Mountain is a prominent center of variegated altered volcanic rocks in west-central Utah. It consists of the eroded remnants of a hypogene alunite deposit that, at ???21 Ma, replaced intermediate-composition lava flows. The alunite formed in steam-heated conditions above the upwelling limb of a convection cell that was one of at least six spaced at 3- to 4-km intervals around the margin of a monzonite stock. Big Rock Candy Mountain is horizontally zoned outward from an alunite core to respective kaolinite, dickite, and propylite envelopes. The altered rocks are also vertically zoned from a lower pyrite-propylite assemblage upward through assemblages successively dominated by hypogene alunite, jarosite, and hematite, to a flooded silica cap. This hydrothermal assemblage is undergoing natural destruction in a steep canyon downcut by the Sevier River in Marysvale Canyon. Integrated geological, mineralogical, spectroscopic remote sensing using AVIRIS data, Ar radiometric, and stable isotopic studies trace the hypogene origin and supergene destruction of the deposit and permit distinction of primary (hydrothermal) and secondary (weathering) processes. This destruction has led to the formation of widespread supergene gypsum in cross-cutting fractures and as surficial crusts, and to natrojarosite, that gives the mountain its buff coloration along ridges facing the canyon. A small spring, Lemonade Spring, with a pH of 2.6 and containing Ca, Mg, Si, Al, Fe, Mn, Cl, and SO4, also occurs near the bottom of the canyon. The 40Ar/39 Ar age (21.32??0.07 Ma) of the alunite is similar to that for other replacement alunites at Marysvale. However, the age spectrum contains evidence of a 6.6-Ma thermal event that can be related to the tectonic activity responsible for the uplift that led to the downcutting of Big Rock Candy Mountain by the Sevier River. This ???6.6 Ma event also is present in the age spectrum of supergene natrojarosite forming today, and probably dates

  9. Male reproductive fitness and queen polyandry are linked to variation in the supergene Gp-9 in the fire ant Solenopsis invicta

    PubMed Central

    Lawson, Lucinda P.; Vander Meer, Robert K.; Shoemaker, DeWayne

    2012-01-01

    Supergenes are clusters of tightly linked loci maintained in specific allelic combinations to facilitate co-segregation of genes governing adaptive phenotypes. In species where strong selection potentially operates at different levels (e.g. eusocial Hymenoptera), positive selection acting within a population to maintain specific allelic combinations in supergenes may have unexpected consequences for some individuals, including the preservation of disadvantageous traits. The nuclear gene Gp-9 in the invasive fire ant Solenopsis invicta is part of a non-recombining, polymorphic supergene region associated with polymorphism in social organization as well as traits affecting physiology, fecundity and behaviour. We show that both male reproductive success and facultative polyandry in queens have a simple genetic basis and are dependent on male Gp-9 genotype. Gp-9b males are unable to maintain exclusive reproductive control over their mates such that queens mated to Gp-9b males remain highly receptive to remating. Queens mated to multiple Gp-9B males are rare. This difference appears to be independent of mating plug production in fertile males of each Gp-9 genotype. However, Gp-9b males have significantly lower sperm counts than Gp-9B males, which could be a cue to females to seek additional mates. Despite the reduced fitness of Gp-9b males, polygyne worker-induced selective mortality of sexuals lacking b-like alleles coupled with the overall success of the polygyne social form act to maintain the Gp-9b allele within nature. Our findings highlight how strong worker-induced selection acting to maintain the Gp-9b allele in the polygyne social form may simultaneously result in reduced reproductive fitness for individual sexual offspring. PMID:22535783

  10. [sup 40]Ar/[sup 39]Ar analysis of supergene jarosite and alunite: Implications to the paleoweathering history of the western USA and West Africa

    SciTech Connect

    Vasconcelos, P.M.; Brimhall, G.H. ); Becker, T.A.; Renne, P.R. )

    1994-01-01

    Supergene alunite (KAl[sub 3](SO[sub 4])[sub 2](OH)[sub 6]) and jarosite (KFe[sub 3](SO[sub 4])[sub 2](OH)[sub 6]) are often precipitated during the oxidation of sulfide-bearing rocks by meteoric solutions. Dating of these phases by the [sup 40]Ar/[sup 39]Ar method allows timing of the progression of the oxidation front during chemical weathering. Fine-scale laser-heating [sup 40]Ar/[sup 39]Ar dating of hypogene alunite and supergene jarosites allows to precisely and accurately time hydrothermal alteration and subsequent supergene oxidation in Goldfield, Nevada. The results indicate that pervasive weathering occurred in the western USA during the Late Miocene ([approximately] 10 Ma ago). Similar application of this technique to the study of weathering and laterite formation in West Africa indicates that the last pervasive oxidation event recorded in the weathering profile in this area also occurred in the Miocene ([approximately] 13 Ma ago). The occurrence of a pervasive Mid to Late Miocene oxidation event recorded in these weathering profiles in the western USA and Africa, and also previously measured in Brazil and Chile, indicates that climatic conditions at that time were conducive to worldwide development of deep weathering sequences. Subsequent weathering processes have not been as pervasive as the late Miocene event, indicating a general climatic transition to cooler, drier climates in most of the areas studied. The results indicate that deep weathering profiles reflect past climatic conditions and may not be directly linked to the present climates.

  11. Male reproductive fitness and queen polyandry are linked to variation in the supergene Gp-9 in the fire ant Solenopsis invicta.

    PubMed

    Lawson, Lucinda P; Vander Meer, Robert K; Shoemaker, Dewayne

    2012-08-22

    Supergenes are clusters of tightly linked loci maintained in specific allelic combinations to facilitate co-segregation of genes governing adaptive phenotypes. In species where strong selection potentially operates at different levels (e.g. eusocial Hymenoptera), positive selection acting within a population to maintain specific allelic combinations in supergenes may have unexpected consequences for some individuals, including the preservation of disadvantageous traits. The nuclear gene Gp-9 in the invasive fire ant Solenopsis invicta is part of a non-recombining, polymorphic supergene region associated with polymorphism in social organization as well as traits affecting physiology, fecundity and behaviour. We show that both male reproductive success and facultative polyandry in queens have a simple genetic basis and are dependent on male Gp-9 genotype. Gp-9(b) males are unable to maintain exclusive reproductive control over their mates such that queens mated to Gp-9(b) males remain highly receptive to remating. Queens mated to multiple Gp-9(B) males are rare. This difference appears to be independent of mating plug production in fertile males of each Gp-9 genotype. However, Gp-9(b) males have significantly lower sperm counts than Gp-9(B) males, which could be a cue to females to seek additional mates. Despite the reduced fitness of Gp-9(b) males, polygyne worker-induced selective mortality of sexuals lacking b-like alleles coupled with the overall success of the polygyne social form act to maintain the Gp-9(b) allele within nature. Our findings highlight how strong worker-induced selection acting to maintain the Gp-9(b) allele in the polygyne social form may simultaneously result in reduced reproductive fitness for individual sexual offspring.

  12. Liquid Crystalline Nanodispersions Functionalized with Cell-Penetrating Peptides for Topical Delivery of Short-Interfering RNAs: A Proposal for Silencing a Pro-Inflammatory Cytokine in Cutaneous Diseases.

    PubMed

    Petrilli, R; Eloy, J O; Praça, F S G; Del Ciampo, J O; Fantini, M A C; Fonseca, M J V; Bentley, M V L B

    2016-05-01

    Short-interfering RNAs (siRNAs) are a potential strategy for the treatment of cutaneous diseases. In this context, liquid crystalline nanoparticles functionalized with specific proteins and peptide-transduction domains (PTDs), which act as penetration enhancers, are a promising carrier for siRNA delivery through the skin. Herein, hexagonal phase liquid crystal nanoparticles based on monoolein (MO) and/or oleic acid (OA) containing (or lacking) the cationic polymer polyethylenimine (PEI) and the cationic lipid oleylamine (OAM) were functionalized with the membrane transduction peptides transcriptional activator (TAT) or penetratin (PNT). These nanoparticles were complexed with siRNA and characterized by particle size, polydispersity, zeta potential, complexation efficiency and siRNA release. The formulations containing cationic agents presented positive zeta potentials, sizes on the nanometer scale, and complexed siRNAs at concentrations of 10 μM; these agents were successfully released in a heparin competition assay. Cell culture studies demonstrated that nanoparticles composed of MO:OA:PEI functionalized with TAT were the most efficient at transfecting L929 cells, and the uptake efficiency was enhanced by TAT peptide functionalization. Thereafter, the selected formulations were evaluated for in vivo skin irritation, penetration and in vivo efficacy using a chemically induced inflammatory animal model. These nanoparticles did not irritate the skin and provided higher siRNA penetration and delivery into the skin than control formulations. Additionally, efficacy studies in the animal model showed that the association of TAT with the nanodispersion provided higher suppression of tumor necrosis factor (TNF)-α. Thus, the development of liquid crystalline nanodispersions containing TAT may lead to improved topical siRNA delivery for the treatment of inflammatory skin diseases.

  13. Antinociceptive effects of analgesic-antitumor peptide (AGAP), a neurotoxin from the scorpion Buthus martensii Karsch, on formalin-induced inflammatory pain through a mitogen-activated protein kinases-dependent mechanism in mice.

    PubMed

    Mao, Qinghong; Ruan, Jiaping; Cai, Xueting; Lu, Wuguang; Ye, Juan; Yang, Jie; Yang, Yang; Sun, Xiaoyan; Cao, Junli; Cao, Peng

    2013-01-01

    In the present study, we investigated the anti-nociceptive effect and the underlying mechanism of the analgesic-antitumor peptide (AGAP), a neurotoxin from the scorpion Buthus martensii Karsch. AGAP in doses of 0.2, 1 and 5 µg was injected intraplantarly (i.pl.) before formalin injection 10 min at the same site. The suppression by intraplantar injection of AGAP on formalin-induced spontaneous nociceptive behaviors was investigated. The results show that AGAP could dose-dependently inhibit formalin-induced two-phase spontaneous flinching response. To investigate the mechanism of action of treatment with AGAP in inflammatory pain, the expressions of peripheral and spinal phosphorylated mitogen-activated protein kinases (phospho-MAPKs) including p-p38, p-ERK and p-JNK were examined. We found that formalin increased the expressions of peripheral and spinal MAPKs, which were prevented by pre-intraplantar injection of AGAP in inflammation pain model in mice. AGAP could also decrease the expression of spinal Fos induced by formalin. Furthermore, combinations the lower doses of the inhibitors of MAPKs (U0126, SP600125, or SB203580 0.1 µg) with the lower dose of AGAP (0.2 µg), the results suggested that AGAP could potentiate the effects of the inhibitors of MAPKs on the inflammatory pain. The present results indicate that pre-intraplantar injection of AGAP prevents the inflammatory pain induced by formalin through a MAPKs-mediated mechanism in mice.

  14. The 5A apolipoprotein A-I mimetic peptide displays anti-inflammatory and antioxidant properties in vivo and in vitro

    PubMed Central

    Tabet, Fatiha; Remaley, Alan T.; Segaliny, Aude I.; Millet, Jonathan; Yan, Ling; Nakhla, Shirley; Barter, Philip J.; Rye, Kerry-Anne; Lambert, Gilles

    2010-01-01

    Objectives The apolipoprotein (apo) A-I mimetic peptide 5A is highly specific for ABCA1-transporter mediated cholesterol efflux. We investigated whether the 5A peptide shares other beneficial features of apoA-I, such as protection against inflammation and oxidation. Methods New-Zealand White rabbits received an infusion of apoA-I, reconstituted HDL containing apoA-I ((A-I)rHDL) or the 5A peptide complexed with phospholipids (PLPC), prior to inserting a collar around the carotid artery. Human coronary artery endothelial cells (HCAECs) were incubated with (A-I)rHDL or 5A/PLPC prior to TNFa stimulation. Results ApoA-I, (A-I)rHDL and 5A/PLPC reduced the collar mediated increase in (i) endothelial expression of cell adhesion molecules VCAM-1 and ICAM-1, (ii) O2− production as well as the expression of the Nox4 catalytic subunits of the NADPH oxidase, and (iii) infiltration of circulating neutrophils into the carotid intima-media. In HCAECs, both 5A/PLPC and (A-I)rHDL inhibited TNFa induced ICAM-1 and VCAM-1 expression as well as the NF-κB signalling cascade and O2− production. The effects of the 5A/PLPC complex were no longer apparent in HCAECs knocked down for ABCA1. Conclusion Like apoA-I, the 5A peptide inhibits acute inflammation and oxidative stress in rabbit carotids and HCAECs. In vitro, the 5A peptide exerts these beneficial effects through interaction with ABCA1. PMID:19965776

  15. The status of supergenes in the 21st century: recombination suppression in Batesian mimicry and sex chromosomes and other complex adaptations.

    PubMed

    Charlesworth, Deborah

    2016-01-01

    I review theoretical models for the evolution of supergenes in the cases of Batesian mimicry in butterflies, distylous plants and sex chromosomes. For each of these systems, I outline the genetic evidence that led to the proposal that they involve multiple genes that interact during 'complex adaptations', and at which the mutations involved are not unconditionally advantageous, but show advantages that trade-off against some disadvantages. I describe recent molecular genetic studies of these systems and questions they raise about the evolution of suppressed recombination. Nonrecombining regions of sex chromosomes have long been known, but it is not yet fully understood why recombination suppression repeatedly evolved in systems in distantly related taxa, but does not always evolve. Recent studies of distylous plants are tending to support the existence of recombination-suppressed genome regions, which may include modest numbers of genes and resemble recently evolved sex-linked regions. For Batesian mimicry, however, molecular genetic work in two butterfly species suggests a new supergene scenario, with a single gene mutating to produce initial adaptive phenotypes, perhaps followed by modifiers specifically refining and perfecting the new phenotype.

  16. The cell-penetrating peptide domain from human heparin-binding epidermal growth factor-like growth factor (HB-EGF) has anti-inflammatory activity in vitro and in vivo

    SciTech Connect

    Lee, Jue-Yeon; Seo, Yoo-Na; Park, Hyun-Jung; Park, Yoon-Jeong; Chung, Chong-Pyoung

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer HBP sequence identified from HB-EGF has cell penetration activity. Black-Right-Pointing-Pointer HBP inhibits the NF-{kappa}B dependent inflammatory responses. Black-Right-Pointing-Pointer HBP directly blocks phosphorylation and degradation of I{kappa}B{alpha}. Black-Right-Pointing-Pointer HBP inhibits nuclear translocation of NF-{kappa}B p65 subunit. -- Abstract: A heparin-binding peptide (HBP) sequence from human heparin-binding epidermal growth factor-like growth factor (HB-EGF) was identified and was shown to exhibit cell penetration activity. This cell penetration induced an anti-inflammatory reaction in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. HBP penetrated the cell membrane during the 10 min treatment and reduced the LPS-induced production of nitric oxide (NO), inducible nitric oxide synthase (iNOS), and cytokines (TNF-{alpha} and IL-6) in a concentration-dependent manner. Additionally, HBP inhibited the LPS-induced upregulation of cytokines, including TNF-{alpha} and IL-6, and decreased the interstitial infiltration of polymorphonuclear leukocytes in a lung inflammation model. HBP inhibited NF-{kappa}B-dependent inflammatory responses by directly blocking the phosphorylation and degradation of I{kappa}B{alpha} and by subsequently inhibiting the nuclear translocation of the p65 subunit of NF-{kappa}B. Taken together, this novel HBP may be potentially useful candidate for anti-inflammatory treatments and can be combined with other drugs of interest to transport attached molecules into cells.

  17. Early prediction of rheumatoid arthritis by magnetic resonance imaging in the absence of anti-cyclic citrullinated peptide antibodies and radiographic erosions in undifferentiated inflammatory arthritis patients: a prospective study.

    PubMed

    Ji, Lanlan; Li, Guangtao; Xu, Yufeng; Zhou, Wei; Zhang, Zhuoli

    2015-11-01

    To assess the practicability of magnetic resonance imaging (MRI) in confirming the diagnosis of clinically suspected rheumatoid arthritis (RA), when anti-cyclic citrullinated peptide antibody and radiographic erosions are absent. We prospectively involved 31 treatment-naive patients with early inflammatory arthritis. At the initial visit, X-rays and gadolinium-enhanced MRI of both hands, as well as serological examinations and acute phase reactants were performed. The scores of synovitis, bone edema, bone erosion and tenosynovitis of metacarpophalangeal and wrist joints were evaluated using the RA-MRI scoring system. For all the patients, radiographs at baseline were normal and anti-cyclic citrullinated peptide antibodies were negative. At the end of follow-up(median 15 months, range 12-20 months), 22 patients were diagnosed as having RA according to 1987 American College of Rheumatology criteria. Bone edema, erosions, synovitis and tenosynovitis were observed in all the patients. However, the frequency of symmetric synovitis in wrists was significantly higher in the RA group. Moreover this group turned out to have significantly higher MRI bone erosion score in wrists. Further, receiver operating characteristic curve analysis revealed a positive wrist bone erosion score at 5, with a specificity of 78% and a sensitivity of 68%. There was no significant difference between the two groups with respect to metacarpophalangeal synovitis, metacarpophalangeal bone erosion, bone edema or tenosynovitis. MRI evidence of symmetric synovitis at wrist and a high bone erosion score at that site may assist in making an early diagnosis of RA in those patients who are negative for anti-cyclic citrullinated peptide antibody. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  18. (Lipo)polysaccharide interactions of antimicrobial peptides.

    PubMed

    Schmidtchen, Artur; Malmsten, Martin

    2015-07-01

    Due to rapidly increasing resistance development against conventional antibiotics, as well as problems associated with diseases either triggered or deteriorated by infection, antimicrobial and anti-inflammatory peptides have attracted considerable interest during the last few years. While there is an emerging understanding of the direct antimicrobial function of such peptides through bacterial membrane destabilization, the mechanisms of their anti-inflammatory function are less clear. We here summarize some recent results obtained from our own research on anti-inflammatory peptides, with focus on peptide-(lipo)polysaccharide interactions.

  19. Antimicrobial and anti-inflammatory effects of Cecropin A(1-8)-Magainin2(1-12) hybrid peptide analog p5 against Malassezia furfur infection in human keratinocytes.

    PubMed

    Ryu, Sunhyo; Choi, Soon-Yong; Acharya, Samudra; Chun, Young-Jin; Gurley, Catherine; Park, Yoonkyung; Armstrong, Cheryl A; Song, Peter I; Kim, Beom-Joon

    2011-08-01

    The lipophilic fungus Malassezia furfur (M. furfur) is a commensal microbe associated with several chronic diseases such as pityriasis versicolor, folliculitis, and seborrheic dermatitis. Because M. furfur-related diseases are difficult to treat and require prolonged use of medications, the treatment for M. furfur-related skin diseases is supposed to gain control over M. furfur growth and the inflammation associated with it, as well as to prevent secondary infections. In this study, we investigated the antifungal and anti-inflammatory effects of cecropin A(1-8)-magainin 2(1-12) hybrid peptide analog P5 on M. furfur. The minimal inhibitory concentration of P5 against M. furfur was 0.39 μM, making it 3-4 times more potent than commonly used antifungal agents such as ketoconazole (1.5 μM) or itraconazole (1.14 μM). P5 efficiently inhibited the expression of IL-8 and Toll-like receptor 2 in M. furfur-infected human keratinocytes without eukaryotic cytotoxicity at its fungicidal concentration. Moreover, P5 significantly downregulated NF-κB activation and intracellular calcium fluctuation, which are closely related with enhanced responses of keratinocyte inflammation induced by M. furfur infection. Taken together, these observations suggest P5 may be a potential therapeutic agent for M. furfur-associated human skin diseases because of its distinct antifungal and anti-inflammatory action.

  20. Prevention of the β-amyloid peptide-induced inflammatory process by inhibition of double-stranded RNA-dependent protein kinase in primary murine mixed co-cultures

    PubMed Central

    2011-01-01

    Background Inflammation may be involved in the pathogenesis of Alzheimer's disease (AD). There has been little success with anti-inflammatory drugs in AD, while the promise of anti-inflammatory treatment is more evident in experimental models. A new anti-inflammatory strategy requires a better understanding of molecular mechanisms. Among the plethora of signaling pathways activated by β-amyloid (Aβ) peptides, the nuclear factor-kappa B (NF-κB) pathway could be an interesting target. In virus-infected cells, double-stranded RNA-dependent protein kinase (PKR) controls the NF-κB signaling pathway. It is well-known that PKR is activated in AD. This led us to study the effect of a specific inhibitor of PKR on the Aβ42-induced inflammatory response in primary mixed murine co-cultures, allowing interactions between neurons, astrocytes and microglia. Methods Primary mixed murine co-cultures were prepared in three steps: a primary culture of astrocytes and microglia for 14 days, then a primary culture of neurons and astrocytes which were cultured with microglia purified from the first culture. Before exposure to Aβ neurotoxicity (72 h), co-cultures were treated with compound C16, a specific inhibitor of PKR. Levels of tumor necrosis factor-α (TNFα), interleukin (IL)-1β, and IL-6 were assessed by ELISA. Levels of PT451-PKR and activation of IκB, NF-κB and caspase-3 were assessed by western blotting. Apoptosis was also followed using annexin V-FITC immunostaining kit. Subcellular distribution of PT451-PKR was assessed by confocal immunofluorescence and morphological structure of cells by scanning electron microscopy. Data were analysed using one-way ANOVA followed by a Newman-Keuls' post hoc test Results In these co-cultures, PKR inhibition prevented Aβ42-induced activation of IκB and NF-κB, strongly decreased production and release of tumor necrosis factor (TNFα) and interleukin (IL)-1β, and limited apoptosis. Conclusion In spite of the complexity of the

  1. Anti-inflammatory and antinociceptive action of the dimeric enkephalin peptide biphalin in the mouse model of colitis: new potential treatment of abdominal pain associated with inflammatory bowel diseases.

    PubMed

    Sobczak, Marta; Pilarczyk, Andrzej; Jonakowski, Mateusz; Jarmuż, Agata; Sałaga, Maciej; Lipkowski, Andrzej W; Fichna, Jakub

    2014-10-01

    Biphalin, a mixed MOP/DOP agonist, displays a potent antinociceptive activity in numerous animal models of pain. The aim of the study was to characterize the anti-inflammatory and antinociceptive action of biphalin in the mouse models of colitis. The anti-inflammatory effect of biphalin (5mg/kg, twice daily, i.c. and i.p.) was characterized in a semi-chronic mouse model of colitis, induced by i.c. injection of trinitrobenzenesulfonic acid (TNBS). The antinociceptive action of biphalin (5mg/kg, i.p. and i.c.) in inflamed mice was assessed in mustard oil-induced model of visceral pain and in the hot plate test. In the semi-chronic mouse model of colitis, biphalin i.c. (5mg/kg), but not i.p. improved colitis macroscopic score (2.88±0.19 and 4.99±0.80 units for biphalin and vehicle treated animals, respectively). Biphalin injected i.p. and i.c. (5mg/kg) displayed a potent antinociceptive action in the mustard oil-induced pain test. In the hot plate test, biphalin (5mg/kg, i.p.) produced a potent antinociceptive activity in inflamed mice, suggesting central site of action. Our data suggest that biphalin may become a novel opioid-based analgesic agent in IBD therapy and warrant further investigation of its pharmacological profile.

  2. Discovery of non-peptide, small molecule antagonists of α9α10 nicotinic acetylcholine receptors as novel analgesics for the treatment of neuropathic and tonic inflammatory pain.

    PubMed

    Zheng, Guangrong; Zhang, Zhenfa; Dowell, Cheryl; Wala, Elzbieta; Dwoskin, Linda P; Holtman, Joseph R; McIntosh, J Michael; Crooks, Peter A

    2011-04-15

    A series of azaaromatic quaternary ammonium analogs has been discovered as potent and selective α9α10 nicotinic acetylcholine receptor (nAChR) antagonists. The preliminary structure-activity relationships of these analogs suggest that increased rigidity in the linker units results in higher potency in inhibition of α9α10 nAChRs and greater selectivity over α7 nAChRs. These analogs represent a new class of analgesic for the treatment of neuropathic and tonic inflammatory pain.

  3. LL-37-derived short antimicrobial peptide KR-12-a5 and its d-amino acid substituted analogs with cell selectivity, anti-biofilm activity, synergistic effect with conventional antibiotics, and anti-inflammatory activity.

    PubMed

    Kim, Eun Young; Rajasekaran, Ganesan; Shin, Song Yub

    2017-08-18

    KR-12-a5 is a 12-meric α-helical antimicrobial peptide (AMP) with dual antimicrobial and anti-inflammatory activities designed from human cathelicidin LL-37. We designed and synthesized a series of d-amino acid-substituted analogs of KR-12-a5 with the aim of developing novel α-helical AMPs that possess higher cell selectivity than KR-12-a5, while maintaining the anti-inflammatory activity. d-amino acid incorporation into KR-12-a5 induced a significant improvement in the cell selectivity by 2.6- to 13.6-fold as compared to KR-12-a5, while maintaining the anti-inflammatory activity. Among the three analogs, KR-12-a5 (6-(D)L) with d-amino acid in the polar-nonpolar interface (Leu(6)) showed the highest cell selectivity (therapeutic index: 61.2). Similar to LL-37, KR-12-a5 and its analogs significantly inhibited the expression and secretion of NO, TNF-α, IL-6 and MCP-1 from LPS-stimulated RAW264.7 cells. KR-12-a5 and its analogs showed a more potent antimicrobial activity against antibiotic-resistant bacteria, including clinically isolated MRSA, MDRPA, and VREF than LL-37 and melittin. Furthermore, compared to LL-37, KR-12-a5 and its analogs showed greater synergistic effects with conventional antibiotics, such as chloramphenicol, ciprofloxacin, and oxacillin against MDRPA; KR-12-a5 and its analogs had a FICI range between 0.25 and 0.5, and LL-37 had a range between 0.75 and 1.5. KR-12-a5 and its analogs were found to be more effective anti-biofilm agents against MDRPA than LL-37. In addition, KR-12-a5 and its analogs maintained antimicrobial activity in physiological salts and human serum. SYTOX Green uptake and membrane depolarization studies revealed that KR-12-a5 and its analogs kills microbial cells by permeabilizing the cell membrane and damaging membrane integrity. Taken together, our results suggest that KR-12-a5 and its analogs can be developed further as novel antimicrobial/anti-inflammatory agents to treat antibiotic-resistant infections. Copyright

  4. Comparison of Two Assays to Determine Anti-Citrullinated Peptide Antibodies in Rheumatoid Arthritis in relation to Other Chronic Inflammatory Rheumatic Diseases: Assaying Anti-Modified Citrullinated Vimentin Antibodies Adds Value to Second-Generation Anti-Citrullinated Cyclic Peptides Testing

    PubMed Central

    Díaz-Toscano, Miriam Lizette; Olivas-Flores, Eva Maria; Zavaleta-Muñiz, Soraya Amali; Gamez-Nava, Jorge Ivan; Cardona-Muñoz, Ernesto German; Ponce-Guarneros, Manuel; Castro-Contreras, Uriel; Nava, Arnulfo; Salazar-Paramo, Mario; Celis, Alfredo; Fajardo-Robledo, Nicte Selene; Corona-Sanchez, Esther Guadalupe; Gonzalez-Lopez, Laura

    2014-01-01

    Determination of anti-citrullinated peptide antibodies (ACPA) plays a relevant role in the diagnosis of rheumatoid arthritis (RA). To date, it is still unclear if the use of several tests for these autoantibodies in the same patient offers additional value as compared to performing only one test. Therefore, we evaluated the performance of using two assays for ACPA: second-generation anti-citrullinated cyclic peptides antibodies (anti-CCP2) and anti-mutated citrullinated vimentin (anti-MCV) antibodies for the diagnosis of RA. We compared three groups: RA (n = 142), chronic inflammatory disease (CIRD, n = 86), and clinically healthy subjects (CHS, n = 56) to evaluate sensitivity, specificity, predictive values, and likelihood ratios (LR) of these two assays for the presence of RA. A lower frequency of positivity for anti-CCP2 was found in RA (66.2%) as compared with anti-MCV (81.0%). When comparing RA versus other CIRD, sensitivity increased when both assays were performed. This strategy of testing both assays had high specificity and LR+. We conclude that adding the assay of anti-MCV antibodies to the determination of anti-CCP2 increases the sensitivity for detecting seropositive RA. Therefore, we propose the use of both assays in the initial screening of RA in longitudinal studies, including early onset of undifferentiated arthritis. PMID:25025037

  5. Comparison of two assays to determine anti-citrullinated peptide antibodies in rheumatoid arthritis in relation to other chronic inflammatory rheumatic diseases: assaying anti-modified citrullinated vimentin antibodies adds value to second-generation anti-citrullinated cyclic peptides testing.

    PubMed

    Díaz-Toscano, Miriam Lizette; Olivas-Flores, Eva Maria; Zavaleta-Muñiz, Soraya Amali; Gamez-Nava, Jorge Ivan; Cardona-Muñoz, Ernesto German; Ponce-Guarneros, Manuel; Castro-Contreras, Uriel; Nava, Arnulfo; Salazar-Paramo, Mario; Celis, Alfredo; Fajardo-Robledo, Nicte Selene; Corona-Sanchez, Esther Guadalupe; Gonzalez-Lopez, Laura

    2014-01-01

    Determination of anti-citrullinated peptide antibodies (ACPA) plays a relevant role in the diagnosis of rheumatoid arthritis (RA). To date, it is still unclear if the use of several tests for these autoantibodies in the same patient offers additional value as compared to performing only one test. Therefore, we evaluated the performance of using two assays for ACPA: second-generation anti-citrullinated cyclic peptides antibodies (anti-CCP2) and anti-mutated citrullinated vimentin (anti-MCV) antibodies for the diagnosis of RA. We compared three groups: RA (n = 142), chronic inflammatory disease (CIRD, n = 86), and clinically healthy subjects (CHS, n = 56) to evaluate sensitivity, specificity, predictive values, and likelihood ratios (LR) of these two assays for the presence of RA. A lower frequency of positivity for anti-CCP2 was found in RA (66.2%) as compared with anti-MCV (81.0%). When comparing RA versus other CIRD, sensitivity increased when both assays were performed. This strategy of testing both assays had high specificity and LR+. We conclude that adding the assay of anti-MCV antibodies to the determination of anti-CCP2 increases the sensitivity for detecting seropositive RA. Therefore, we propose the use of both assays in the initial screening of RA in longitudinal studies, including early onset of undifferentiated arthritis.

  6. Activation of IKK/NF-κB provokes renal inflammatory responses in guanylyl cyclase/natriuretic peptide receptor-A gene-knockout mice

    PubMed Central

    Das, Subhankar; Periyasamy, Ramu

    2012-01-01

    The present study was aimed at determining the consequences of the disruption of guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene (Npr1) on proinflammatory responses of nuclear factor kappa B, inhibitory kappa B kinase, and inhibitory kappa B alpha (NF-κB, IKK, IκBα) in the kidneys of mutant mice. The results showed that the disruption of Npr1 enhanced the renal NF-κB binding activity by 3.8-fold in 0-copy (−/−) mice compared with 2-copy (+/+) mice. In parallel, IKK activity and IκBα protein phosphorylation were increased by 8- and 11-fold, respectively, in the kidneys of 0-copy mice compared with wild-type mice. Interestingly, IκBα was reduced by 80% and the expression of proinflammatory cytokines and renal fibrosis were significantly enhanced in 0-copy mice than 2-copy mice. Treatment of 0-copy mice with NF-κB inhibitors andrographolide, pyrrolidine dithiocarbamate, and etanercept showed a substantial reduction in renal fibrosis, attenuation of proinflammatory cytokines gene expression, and significantly reduced IKK activity and IkBα phosphorylation. These findings indicate that the systemic disruption of Npr1 activates the renal NF-κB pathways in 0-copy mice, which transactivates the expression of various proinflammatory cytokines to initiate renal remodeling; however, inhibition of NF-κB pathway repairs the abnormal renal pathology in mutant mice. PMID:22318993

  7. Adiponectin-derived active peptide ADP355 exerts anti-inflammatory and anti-fibrotic activities in thioacetamide-induced liver injury

    PubMed Central

    Wang, Huafeng; Zhang, Huan; Zhang, Zimu; Huang, Biao; Cheng, Xixi; Wang, Dan; la Gahu, Zha; Xue, Zhenyi; Da, Yurong; Li, Daiqing; Yao, Zhi; Gao, Fei; Xu, Aimin; Zhang, Rongxin

    2016-01-01

    Adiponectin is an adipocyte-derived circulating protein with beneficial effects on injured livers. Adiponectin-deficient (adipo(−/−)) mice develop enhanced liver fibrosis, suggesting that adiponectin could be a therapeutic target for liver injury. In the present study, we investigated the protective role of ADP355, an adiponectin-based active short peptide, in thioacetamide (TAA)-induced acute injury and chronic liver fibrosis in mice. ADP355 remarkably reduced TAA-induced necroinflammation and liver fibrosis. ADP355 treatment increased liver glycogen, decreased serum alanine transaminase and alkaline phosphatase activity, and promoted body weight gain, hyper-proliferation and hypo-apoptosis. In addition, ADP355 administration suppressed the TAA-induced activation of hepatic stellate cells and macrophages in the liver. These were associated with the inactivation of TGF-β1/SMAD2 signaling and the promotion of AMPK and STAT3 signaling. Sensitivity of adipo(−/−) mice to chronic liver injury was decreased with ADP355. In conclusion, ADP355 could mimic adiponectin’s action and may be suitable for the preclinical or clinical therapy of chronic liver injury. PMID:26777428

  8. The Leu7Pro polymorphism of the signal peptide of neuropeptide Y (NPY) gene is associated with increased levels of inflammatory markers preceding vascular complications in patients with type 2 diabetes.

    PubMed

    Jaakkola, U; Kakko, T; Seppälä, H; Vainio-Jylhä, E; Vahlberg, T; Raitakari, O T; Kallio, J

    2010-12-01

    The Leucine7 to Proline7 (Leu7Pro) polymorphism of the signal peptide of neuropeptide Y (NPY) increases risk for vascular complications in diabetes. Diabetes is associated with low-grade inflammation, which has an important role in the development of atherosclerosis. Currently, we followed diabetes patients to investigate, if the Pro7 allele is associated with the inflammation related to atherosclerosis. In the 5-year follow-up, the genotyped, pair-matched type 2 diabetes patients (12 with the Pro7 allele and 19 without) were investigated using non-invasive ultrasound based methods to measure the development of atherosclerosis (intima media thickness=IMT) and endothelium-dependent (FMD) and -independent nitrate-mediated (NMD) vasodilatation. The development of diabetic complications was followed annually, and the concentrations of inflammatory markers and NPY in plasma were determined. Patients with the Pro7 had increased U-albumin/creatinine (p=0.037), E-selectin (p=0.016), fasting insulin (p=0.011) and HOMA index (p=0.013) but decreased serum amyloid P concentrations (p=0.021). Furthermore, men with the Pro7 had increased CRP (p=0.010) and NPY (p=0.026) concentrations. IMT and FMD were similar in all patients, however, NMD decreased more during the follow-up in the patients with the Pro7 (p=0.002). NPY correlated positively with bIMT [r 0.04 (SE 0.02), p=0.007] and E-selectin negatively with FMD [r -0.05 (S.E 0.02), p=0.039]. Diabetes patients with the Pro7 allele display increased levels of inflammatory molecules and NPY in blood, preceding vascular wall thickening and impaired endothelial dilatation, especially in male patients. Copyright © 2010 Elsevier Inc. All rights reserved.

  9. Effect of flavonoids rich extract of Capparis spinosa on inflammatory involved genes in amyloid-beta peptide injected rat model of Alzheimer's disease.

    PubMed

    Mohebali, Nazanin; Shahzadeh Fazeli, Seyed Abolhassan; Ghafoori, Hossein; Farahmand, Zeinab; MohammadKhani, Elham; Vakhshiteh, Faezeh; Ghamarian, Abdolreza; Farhangniya, Mansoureh; Sanati, Mohammad Hossein

    2016-10-25

    Alzheimer's disease (AD) is one of the most common forms of neurodegenerative diseases. Despite vast ongoing researches focusing on the area, little is known about novel treatments. In this study, we aimed to survey the effects of Capparis spinosa (C. spinosa) extract on amyloid-beta peptide (Aβ)-injected rat. For this purpose, hydroalcoholic extracts of caper leaf and fruit were prepared. Total phenolic content, DPPH, and FRAP assay were accomplished to determine antioxidant activity of C. spinosa. HPLC analysis was conducted to measure rutin and quercetin content of selected parts of the plant. Higher levels of flavonoids were observed in leaves of the plant. Twelve male Wistar Aβ-induced rats were randomly divided in four groups of (1) Aβ(-)/DW(+): Sham-operated group (2) Aβ(+)/DW(+): Aβ-injected group (3) Aβ(+)/RU(+): Standard rutin treatment (4) Aβ(+)/CS(+): C. spinosa extract treatment. After 6 weeks of oral administration, real-time qPCR were conducted to determine APP, BACE-1, PSEN-1, and PSEN-2 genes expression in the hippocampus of rats. HPLC analysis showed high levels of rutin and quercetin in leaves of Capparis. Rutin was 16939.2 ± 0.01 and quercetin was 908.93 ± 0.01 µg/g fresh weight. In fruit, 1019.52 ± 0.01 rutin and 97.86 ± 0.01 µg/g FW quercetin were measured. Expression of BACE-1, APP, PSEN-1, and PSEN-2 genes in comparison with the control group showed significant down regulation. Results of the study demonstrated that C. spinosa has the potential to down regulate inflammation-involved genes in AD, due to its high levels of flavonoids and could be beneficial as a dietary complement in AD patients.

  10. New Csbnd O isotopic data on supergene minerals from the Skorpion and Rosh Pinah ore deposits (Namibia): Genetic and paleoclimatic constraints

    NASA Astrophysics Data System (ADS)

    Arfè, G.; Boni, M.; Balassone, G.; Mondillo, N.; Hinder, G.; Joachimski, M.

    2017-02-01

    Skorpion and Rosh Pinah Zn-(Pb) deposits are hosted in Neoproterozoic rocks that are part of a volcano-sedimentary sequence within the Gariep Belt of southwest Namibia. Skorpion is the largest Zn-nonsulphide mineralization ever discovered. It formed from weathering and oxidation of a volcanic hosted massive sulphide (VMS) protore and mostly consists of Zn-oxidized minerals. Rosh Pinah is a hybrid Zn massive sulphide deposit, with some VMS and Broken Hill-type characteristics and partly weathered in the uppermost part of the massive sulphide lens. We compared the deep oxidation process that occurred at Skorpion with the limited weathering of the Rosh Pinah deposit by studying the carbon and oxygen isotope ratios of supergene carbonates minerals. Twenty three smithsonite samples from the Skorpion deposit and 6 gossanous samples (containing both host dolomite and smithsonite) from the uppermost levels of the Rosh Pinah mine have been analysed. The Skorpion smithsonites form botryoidal crusts overgrown by euhedral calcite crystals. At Rosh Pinah all sampled smithsonites occur in veins within the dolostone host rock. Skorpion smithsonite is characterized by δ13C values strongly variable between -9.1‰ and 0.1‰ VPDB and by a small range in δ18O from 28.0 to 29.9‰ VSMOW. Calcite shows a minor variation in δ13C with values being generally positive (0-1.6‰ VPDB) and δ18O values slightly lower than those of smithsonite (25.4-27.1‰ VSMOW). The analyses of the Rosh Pinah samples show that the host dolomite is characterized by δ18O values ranging from 18.7 to 22.0‰ VSMOW and by negative δ13C values (-5.9 to -2.7‰ VPDB). The carbon isotope ratios of smithsonite, as in Skorpion, are negative (-2.8 to -1.9‰ VPDB) and partly overlapping with those of the host dolomites. The δ18O values (26.7-29.0‰ VSMOW) are on average comparable with the values measured at Skorpion. The similar negative δ13C values of smithsonite and dolomite at Rosh Pinah point to the

  11. Cathelicidin impact on inflammatory cells

    PubMed Central

    Efenberger, Magdalena; Brzezińska-Błaszczyk, Ewa

    2015-01-01

    Cathelicidins, like other antimicrobial peptides, exhibit direct antimicrobial activities against a broad spectrum of microbes, including both Gram-positive and Gram-negative bacteria, enveloped viruses, and fungi. These host-derived peptides kill the invaded pathogens by perturbing their cell membranes and can neutralize biological activities of endotoxin. Nowadays, more and more data indicate that these peptides, in addition to their antimicrobial properties, possess various immunomodulatory activities. Cathelicidins have the potential to influence and modulate, both directly and indirectly, the activity of various cell populations involved in inflammatory processes and in host defense against invading pathogens. They induce migration of neutrophils, monocytes/macrophages, eosinophils, and mast cells and prolong the lifespan of neutrophils. These peptides directly activate inflammatory cells to production and release of different pro-inflammatory and immunoregulatory mediators, cytokines, and chemokines, however cathelicidins might mediate the generation of anti-inflammatory cytokines as well. Cathelicidins also modulate epithelial cell/keratinocyte responses to infecting pathogens. What is more, they affect activity of monocytes, dendritic cells, keratinocytes, or epithelial cells acting in synergy with cytokines or β-defensins. In addition, these peptides indirectly balance TLR-mediated responses of monocytes, macrophages, dendritic cells, epithelial cells, and keratinocytes. This review discusses the role and significance of cathelicidins in inflammation and innate immunity against pathogens. PMID:26557038

  12. Redefining the induction of periodontal tissue regeneration in primates by the osteogenic proteins of the transforming growth factor-β supergene family.

    PubMed

    Ripamonti, U

    2016-12-01

    The molecular bases of periodontal tissue induction and regeneration are the osteogenic proteins of the transforming growth factor-β (TGF-β) supergene family. These morphogens act as soluble mediators for the induction of tissues morphogenesis sculpting the multicellular mineralized structures of the periodontal tissues with functionally oriented ligament fibers into newly formed cementum. Human TGF-β3 (hTGF-β3 ) in growth factor-reduced Matrigel(®) matrix induces cementogenesis when implanted in class II mandibular furcation defects surgically prepared in the non-human primate Chacma baboon, Papio ursinus. The newly formed periodontal ligament space is characterized by running fibers tightly attached to the cementoid surface penetrating as mineralized constructs within the newly formed cementum assembling and initiating within the mineralized dentine. Angiogenesis heralds the newly formed periodontal ligament space, and newly sprouting capillaries are lined by cellular elements with condensed chromatin interpreted as angioblasts responsible for the rapid and sustained induction of angiogenesis. The inductive activity of hTGF-β3 in Matrigel(®) matrix is enhanced by the addition of autogenous morcellated fragments of the rectus abdominis muscle potentially providing myoblastic, pericytic/perivascular stem cells for continuous tissue induction and morphogenesis. The striated rectus abdominis muscle is endowed with stem cell niches in para/perivascular location, which can be dominant, thus imposing stem cell features or stemness to the surrounding cells. This capacity to impose stemness is morphologically shown by greater alveolar bone induction and cementogenesis when hTGF-β3 in Matrigel(®) matrix is combined with morcellated fragments of autogenous rectus abdominis muscle. The induction of periodontal tissue morphogenesis develops as a mosaic structure in which the osteogenic proteins of the TGF-β supergene family singly, synergistically and synchronously

  13. Direct dating of weathering phenomena by [sup 40]Ar/[sup 39]Ar and K-Ar analysis of supergene K-Mn oxides

    SciTech Connect

    Vasconcelos, P.M.; Brimhall, G.H. ); Renne, P.R.; Becker, T.A. )

    1994-03-01

    Potassium-bearing manganese oxides, cryptomelane, K[sub 1-2](Mn[sup 3+]Mn[sup 4+])[sub 8] O[sub 16] [center dot] xH[sub 2]O, and hollandite, (K,Ba)[sub 1-2](Mn[sup 3+],Mn[sup 4+])[sub 8] O[sub 16] [center dot] xH[sub 2]O, are often authigenically precipitated in weathering profiles. Dating of these phases allows timing of the progression of oxidation fronts during weathering and pedogenic processes. Potential problems in manganese oxide dating, such as Ar and/or K losses, excess argon, [sup 39]Ar loss by recoil during neutron irradiation, etc. are addressed. The K-Ar and [sup 40]Ar/[sup 39]Ar analytical results indicate that Ar and/or K losses, excess [sup 40]Ar, and [sup 39]Ar recoil seem not to pose problems in manganese oxide dating. This investigation suggests that the fine scale, laser-probe [sup 40]Ar/[sup 39]Ar technique is most appropriate for dating of weathering phenomena because this technique permits identification of contaminating phases and the presence of multiple generations of weathering minerals in the inherently complex mineral assemblage characteristic of weathering profiles. K-Ar and [sup 40]Ar/[sup 39]Ar dating of supergene K-bearing manganese oxides formed during lateritization of Archean and Proterozoic bedrocks in the Carajas Region, Amazonia, Brazil, indicates that weathering started before 72 [+-] 6 Ma. Petrographic, electron microscope, and electron microprobe investigation reveal multiple generations of manganese oxide precipitation. Age clusters at 65-69, 51-56, 40-43, 33-35, 20, 24, 12-17 Ma, and zero-age (0.2 [+-] 0.2 Ma) suggest episodic precipitation of K-Mn oxides resulting form changing weathering conditions in the Amazon throughout the Cenozoic. K-Ar and [sup 40]Ar/[sup 39]Ar dating of supergene cryptomelane from weathering profiles in eastern Minas Gerais, southeastern Brazil, suggests continuous weathering from 10 to 5.6 Ma ago, possibly reflecting local climatic conditions due to the proximity with the Atlantic Ocean.

  14. Identification of peptide targets in neuromyelitis optica

    PubMed Central

    Yu, Xiaoli; Green, Miyoko; Gilden, Don; Lam, Chiwah; Bautista, Katherine; Bennett, Jeffrey L

    2011-01-01

    Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that predominantly affects the optic nerves and spinal cord. Recombinant antibodies (rAbs) generated from clonally expanded plasma cells in an NMO patient are specific to AQP4 and pathogenic. We screened phage-displayed peptide libraries with these rAbs, and identified 14 high affinity linear and conformational peptides. The linear peptides shared sequence homologies with NMO autoantigen AQP4 on the extracellular surface. Competitive inhibition ELISA and immunocytochemistry demonstrated that these peptides represent epitopes of NMO autoantigen AQP4. Peptide epitopes/mimotopes may have potential uses for disease prognosis, monitoring, and therapy. PMID:21621279

  15. Somatostatin in inflammatory bowel disease

    PubMed Central

    Wilson, J. H. P.

    1997-01-01

    Intestinal inflammation is controlled by various immunomodulating cells, interacting by molecular mediators. Neuropeptides, released by enteric nerve cells and neuroendocrine mucosa cells, are able to affect several aspects of the general and intestinal immune system, with both pro- as well as anti-inflammatory activities. In inflammatory bowel disease (IBD) there is both morphological as well as experimental evidence for involvement of neuropeptides in the pathogenesis. Somatostatin is the main inhibitory peptide in inflammatory processes, and its possible role in IBD is discussed. PMID:18472863

  16. Inflammatory neuropathies.

    PubMed

    Whitesell, Jackie

    2010-09-01

    Inflammatory neuropathies are acquired disorders of peripheral nerves and occasionally of the central nervous system that can affect individuals at any age. The course can be monophasic, relapsing, or progressive. Inflammatory neuropathies are classified as acute or chronic. The acute form reaches a nadir by 4 weeks and the chronic form over 8 weeks or greater. The most common example of an acute inflammatory neuropathy is acute inflammatory demyelinating polyradiculoneuropathy (AIDP), which is part of the Guillain-Barré syndrome (GBS). The most common chronic inflammatory neuropathy is chronic inflammatory demyelinating polyradiculopathy (CIDP). Other chronic inflammatory neuropathies are multifocal motor neuropathy (MMN) and the Lewis-Sumner syndrome. The Fisher syndrome and Bickerstaff brainstem encephalitis occur acutely and have clinical overlap with AIDP.

  17. Age and mineralogy of supergene uranium minerals — Tools to unravel geomorphological and palaeohydrological processes in granitic terrains (Bohemian Massif, SE Germany)

    NASA Astrophysics Data System (ADS)

    Dill, H. G.; Gerdes, A.; Weber, B.

    2010-04-01

    Uranyl phosphates (torbernite, autunite, uranocircite, saleeite) and hydrated uranyl silicates (normal and beta-uranophane) found in various erosion levels and structures in the Late Variscan granites at the western edge of the Bohemian Massif, Germany, were the target of mineralogical investigations and age dating, using conventional and more advanced techniques such as Laser-Ablation-Inductive-Coupled-Plasma Mass Spectrometry (LA-ICP-MS). Supergene U minerals have an edge over other rock-forming minerals for such studies, because of their inherent ‘clock’ and their swift response to chemical and physical environmental changes on different scales. Uraniferous phoscretes and silcretes, can be used to characterize the alkalinity/acidity of meteoric/per descensum fluids and to constrain the redox conditions during geomorphic processes. This study aims to decipher the geomorphological and palaeohydrological regime that granitic rocks of the Central European Variscides (Moldanubian and Saxothuringian zones) went through during the Neogene and Quaternary in the foreland of the rising Alpine mobile fold belt. The study provides an amendment to the current sub-division of the regolith by introducing the term “hydraulith”, made up of percolation and infiltration zones, for the supergene alteration zone in granitic terrains. It undercuts the regolith at the brink of the phreatic to vadose hydrological zones. Based upon the present geomorphological and mineralogical studies a four-stage model is proposed for the evolution of the landscape in a granitic terrain which might also be applicable to other regions of the European Variscides, considering the hydrological facies changes along with paleocurrent and paleoslope in the basement and the development of the fluvial drainage system in the foreland. Stage I (U mineralization in the infiltration zone) is a mirror image of the relic granitic landscape with high-altitude divides and alluvial-fluvial terraces. Its

  18. Fast formation of supergene Mn oxides/hydroxides under acidic conditions in the oxic/anoxic transition zone of a shallow aquifer.

    PubMed

    Schäffner, F; Merten, D; Pollok, K; Wagner, S; Knoblauch, S; Langenhorst, F; Büchel, G

    2015-12-01

    Extensive uranium mining in the former German Democratic Republic (GDR) in eastern Thuringia and Saxony took place during the period of 1946-1990. During mining activities, pelitic sediments rich in organic carbon and uranium were processed and exposed to oxygen. Subsequent pyrite oxidation and acidic leaching lead to partial contamination of the area with heavy metals and acid mine drainage (AMD) even few years after completion of remediation. One of those areas is the former heap Gessen (Ronneburg, Germany) were the residual contamination can be found 10 m under the base of the former heap containing partly permeable drainage channels. Actually, in such a system, a rapid but locally restricted mineralization of Mn oxides takes place under acidic conditions. This formation can be classified as a natural attenuation process as certain heavy metals, e.g., Cd (up to 6 μg/g), Ni (up to 311 μg/g), Co (up to 133 μg/g), and Zn (up to 104 μg/g) are bound to this phases. The secondary minerals occur as colored layers close to the shallow aquifer in glacial sediments and could be identified as birnessite and todorokite as Mn phase. The thermodynamic model shows that even small changes in the system are sufficient to shift either the pH or the Eh in the direction of stable Mn oxide phases in this acidic system. As a consequence of 9-15-year-long formation process (or even less), the supergene mineralization provides a cost-efficient contribution for remediation (natural attenuation) strategies of residual with heavy metals (e.g., Cd, Co, Ni, Zn) contaminated substrates.

  19. Chemical and physical erosion rhythms of the West African Cenozoic morphogenesis: The 39Ar-40Ar dating of supergene K-Mn oxides

    NASA Astrophysics Data System (ADS)

    Beauvais, Anicet; Ruffet, Gilles; HéNocque, Olivier; Colin, Fabrice

    2008-12-01

    Chemical weathering and mechanical erosion are first-order processes of long-term tropical morphogenesis, which is still poorly deciphered for lack of time constraints. We address this issue by laser probe 39Ar-40Ar dating of generations of cryptomelane [K1-2Mn8O16, nH2O] from the manganese ore deposit of Tambao in northern Burkina Faso. This Mn deposit results from the supergene weathering of carbonate and silicate Mn protores underneath lateritic palaeolandsurfaces. It consists of an upper cryptomelane-rich domain and a lower domain where pyrolusite (β-MnO2) is the dominant Mn oxide. The oldest 39Ar-40Ar ages (59-45 Ma) are obtained on surface outcrops while the youngest ones characterize deep oxidation fronts (3.4-2.9 Ma). Apparent correlations of 39Ar-40Ar age groups with δ18O and eustatic curves allow definition of the different stages of morphogenesis. Paleocene-Eocene ages (59-45 Ma) bracket a greenhouse period propitious to bauxitic weathering. The lack of significant ages between ˜45 and 29 Ma characterizes a period dominated by mechanical erosion, during which detrital sediments, including lateritic materials, were accumulated in intracratonic basins allowing the exhumation of a new lateritic landsurface. Two major weathering periods separated by a second erosion episode (24-18 Ma) are also depicted at the end of Oligocene (29-24 Ma) and lower to mid-Miocene (18-11.5 Ma) in the upper domain, during which newly shaped land surfaces conspicuously weathered. The shorter-weathering and erosion episodes recorded in the lower domain from ˜18 to ˜2.9 Ma led to the final geomorphic changes that were conducive to the formation of glacis. The preservation of old cryptomelane (59-45 Ma) in the upper part of the ore deposit indicates a Cenozoic denudation limited to the erosion of previous bauxites, and partly, of ferricretes.

  20. High-grade iron ore at Windarling, Yilgarn Craton: a product of syn-orogenic deformation, hypogene hydrothermal alteration and supergene modification in an Archean BIF-basalt lithostratigraphy

    NASA Astrophysics Data System (ADS)

    Angerer, Thomas; Hagemann, Steffen G.; Danyushevsky, Leonid

    2013-08-01

    , carbonate and quartz to form veins and breccia but did not generate significant volumes of iron ore. Ore stage 4 involved Mesozoic(?) to recent supergene oxidation and hydration in a weathering environment reaching down to depths of ˜100 to maximum 200 m below surface. Supergene ore formation involved goethite replacement of dolomite and quartz as well as martitisation. Important `ground preparation' for supergene modification and upgrade were mainly the formation of steep D1 to D4 structures, steep BIF/basalt margins and particularly the syn-D1 to syn-D2 carbonate alteration of BIF that is most susceptible to supergene dissolution. The Windarling deposits are structurally controlled, supergene-modified hydrothermal iron ore systems that share comparable physical, chemical and ore-forming characteristics to other iron ore deposits in the Yilgarn Craton (e.g. Koolyanobbing, Beebyn in the Weld Range, Mt. Gibson). However, the remarkable variety in pre-, syn- and post-deformational ore textures (relative to D1 and D2) has not been described elsewhere in the Yilgarn and are similar to the ore deposits in high-strain zones, such as of Brazil (Quadrilátero Ferrífero or Iron Quadrangle) and Nigeria. The overall similarity of alteration stages, i.e. the sequence of hydrothermal carbonate introduction and hypogene leaching, with other greenstone belt-hosted iron ore deposits supports the interpretation that syn-orogenic BIF alteration and upgrade was crucial in the formation of hypogene-supergene iron ore deposits in the Yilgarn Craton and possibly in other Archean/Paleoproterozoic greenstone belt settings worldwide.

  1. Effect of muramyl peptides on mitochondrial respiration.

    PubMed

    El-Jamal, N; Bahr, G M; Echtay, K S

    2009-01-01

    Muramyl peptides have been shown to exert several biological activities including potentiation of humoral and cell-mediated immunity and stimulation of natural resistance. The mode of action of muramyl peptides has not been elucidated fully and the immunological activities of some derivatives have been associated with toxic effects, including pyrogenicity and inflammatory reactions. Nevertheless, the impact of muramyl peptides on mitochondrial respiration has never been addressed. In this study, the in vitro effects of muramyl peptides on rat liver mitochondria were examined. Toxic muramyl peptides induced a significant decrease in respiratory control ratio versus non-toxic analogues. These results were confirmed by in vivo studies in mice and were extended to mitochondria isolated from spleens. Our data address, for the first time, the effect of muramyl peptides on mitochondrial bioenergetics. Further studies are required to reveal the mechanism of mitochondrial toxicity in relation to the damaging effects of toxic muramyl peptides.

  2. Criteria for the recognition of pedogenic/supergene and nonpedogenic/hypogene deposits and their relationship to the origin of calcite/opal deposits at Yucca Mountain. Special report No. 14

    SciTech Connect

    Hill, C.A.; Schluter, C.M.; Monger, H.C.

    1993-10-01

    This study is part of the research program of the Yucca Mountain Project intended to provide the State of Nevada with a detailed assessment of the geology and geochemistry of Yucca Mountain and adjacent regions. The purpose of this report is to try and establish criteria for the recognition of pedogenic/supergene deposits of calcite/opal versus non-pedogenic/hypogene deposits of calcite/opal. Far from being of esoteric concern, this subject is of paramount importance to the pedogenic-hypogene debate which rages around the suitability of Yucca Mountain as a high-level radioactive waste repository site.

  3. Bioactive Peptides

    PubMed Central

    Daliri, Eric Banan-Mwine; Oh, Deog H.; Lee, Byong H.

    2017-01-01

    The increased consumer awareness of the health promoting effects of functional foods and nutraceuticals is the driving force of the functional food and nutraceutical market. Bioactive peptides are known for their high tissue affinity, specificity and efficiency in promoting health. For this reason, the search for food-derived bioactive peptides has increased exponentially. Over the years, many potential bioactive peptides from food have been documented; yet, obstacles such as the need to establish optimal conditions for industrial scale production and the absence of well-designed clinical trials to provide robust evidence for proving health claims continue to exist. Other important factors such as the possibility of allergenicity, cytotoxicity and the stability of the peptides during gastrointestinal digestion would need to be addressed. This review discusses our current knowledge on the health effects of food-derived bioactive peptides, their processing methods and challenges in their development. PMID:28445415

  4. Bioactive Peptides.

    PubMed

    Daliri, Eric Banan-Mwine; Oh, Deog H; Lee, Byong H

    2017-04-26

    The increased consumer awareness of the health promoting effects of functional foods and nutraceuticals is the driving force of the functional food and nutraceutical market. Bioactive peptides are known for their high tissue affinity, specificity and efficiency in promoting health. For this reason, the search for food-derived bioactive peptides has increased exponentially. Over the years, many potential bioactive peptides from food have been documented; yet, obstacles such as the need to establish optimal conditions for industrial scale production and the absence of well-designed clinical trials to provide robust evidence for proving health claims continue to exist. Other important factors such as the possibility of allergenicity, cytotoxicity and the stability of the peptides during gastrointestinal digestion would need to be addressed. This review discusses our current knowledge on the health effects of food-derived bioactive peptides, their processing methods and challenges in their development.

  5. Antimicrobial peptides: clinical relevance and therapeutic implications.

    PubMed

    Pinheiro da Silva, Fabiano; Machado, Marcel Cerqueira César

    2012-08-01

    Antimicrobial peptides (AMPs) are molecules that provide protection against environmental pathogens, acting against a large number of microorganisms, including bacteria, fungi, yeast, virus and others. Two major groups of antimicrobial peptides are found in humans: cathelicidins and defensins. Recently, several studies have furnished information that besides their role in infection diseases, antimicrobial peptides play a role in diseases as diverse as inflammatory disorders, autoimmunity and cancer. Here, we discuss the role of antimicrobial peptides and vitamin D have in such complex diseases and propose their use should be more explored in the diagnosis and treatment of such conditions.

  6. Insect peptides - perspectives in human diseases treatment.

    PubMed

    Chowański, Szymon; Adamski, Zbigniew; Lubawy, Jan; Marciniak, Paweł; Pacholska-Bogalska, Joanna; Słocińska, Małgorzata; Spochacz, Marta; Szymczak, Monika; Urbański, Arkadiusz; Walkowiak-Nowicka, Karolina; Rosiński, Grzegorz

    2017-05-26

    Insects are the largest and the most widely distributed group of animals in the world. Their diversity gives rise to an incredible variety of different mechanisms for the regulation of life processes. There are many agents that regulate immunology, reproduction, growth and development or metabolism. Hence, it seems that insects may be a source of numerous substances with utility for the treatment human diseases. Of particular importance in the regulation of insect physiology are peptides, including neuropeptides, peptide hormones and antimicrobial peptides. There are two main ways in which these peptides may be useful. 1) Peptides isolated from insects may become potential therapeutic drugs for different diseases. 2) Many insect peptide hormones show structural or functional homology to mammalian peptide hormones, and comparative studies may provide a new perspective on human disorders. In our review, we focused on three groups of insect-derived peptides: 1) immune-active peptides, 2) peptide hormones and 3) peptides present in venoms. In our review, we show the considerable potential of insect peptides in the search for new solutions for mammalian diseases treatment. We summarize knowledge about the properties of insect peptides against different virulent agents, and their anti-inflammatory or anti-nociceptive properties as well as compare the insect and mammalian/vertebrate peptide endocrine systems to determine the usefulness of knowledge about insect peptide hormones in drug design. The field of possible uses of insect-delivered peptides for the treatment of various human diseases has still not been sufficiently explored. Undoubtedly, more attention should be paid to insects in the search for new drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Hypogene and supergene alteration of the Late Palaeozoic Ratburi Limestone during the Mesozoic and Cenozoic (Thailand, Surat Thani Province). Implications for the concentration of mineral commodities and hydrocarbons

    NASA Astrophysics Data System (ADS)

    Dill, H. G.; Botz, R.; Luppold, F. W.; Henjes-Kunst, F.

    2005-02-01

    An interdisciplinary study of the Upper Carboniferous to Middle Permian Ratburi Group, Peninsular Thailand, is presented. The investigation involved sedimentary petrography, inorganic geochemistry, Sr, C, O isotope analyses, micropalaeontology as well as radio-carbon age dating. Emphasis was placed on the post-depositional evolution of the Ratburi Limestone in the Surat Thani Province. The Holocene chemical residues and the various calcite and dolomite minerals which have formed since the Late Palaeozoic in the Ratburi Limestone are the product of a complex, multistage alteration which is called supergene and hypogene karstifications, respectively. Sedimentation took place in a shelf environment with some reefs evolving during the late Murgabian at the shelf margin. There was no pre-concentration of elements, except for Ca and F during sedimentation. Diagenetic neomorphism and cementation under marine and freshwater conditions caused the Ratburi Limestone to convert into a marble-like rock. Fabric-selective dolomitization is of local scale and has impacted only on part of the Ratburi Limestone during the Lower to Upper Permian. A significant enhancement of pore space and better conduits were generated during the Late Cretaceous epithermal alteration. The most favorable conditions for the accumulation of metals were provided during the high-temperature stage of epithermal alteration when a low-metal concentration with As, Zn, Sb, U, Co and Pb existed. Unlike the other elements, Sb was subject to a multiphase concentration, giving rise to a considerable Sb deposit in the region. The most recent stage of karstification produced numerous caves, dripstones, tufa terraces and encrustations around brine pools in the study area. This alteration originated from per descensum and per ascensum processes which may be traced back to 15,000 years before present. The alteration of the Ratburi Limestone may be subdivided into two parts. The prograde post-depositional alteration

  8. Mineralogical, chemical, and crystallographic properties of supergene jarosite-group minerals from the Xitieshan Pb-Zn sulfide deposit, northern Tibetan Plateau, China

    USGS Publications Warehouse

    Chen, Lei; Li, Jian-Wei; Rye, Robert O.; Benzel, William H.; Lowers, H.A.; He, Ming-Zhong

    2013-01-01

    Supergene jarosite-group minerals are widespread in weathering profiles overlying Pb-Zn sulfide ores at Xitieshan, northern Tibetan Plateau, China. They consist predominantly of K-deficient natrojarosite, with lesser amounts of K-rich natrojarosite and plumbojarosite. Electron microprobe (EMP) analyses, scanning electron microcopy (SEM) investigation, and X-ray mapping reveal that the jarosite-group minerals are characterized by spectacular oscillatory zoning composed of alternating growth bands of K-deficient and K-bearing natrojarosite (K2O >1 wt.%). Plumbojarosite, whenever present, occurs as an overgrowth in the outermost bands, and its composition can be best represented by K0.29Na0.19Pb0.31Fe2.66Al0.22(SO4)1.65(PO4)0.31(AsO4)0.04(OH)7.37. The substitution of monovalent for divalent cations at the A site of plumbojarosite is charge balanced by the substitution of five-valent for six-valent anions in XO,4/sub> at the X site. Thermogravimetric analysis (TGA) of representative samples reveal mass losses of 11.46 wt.% at 446.6 °C and 21.42 wt.% at 683.4 °C due to dehydroxylation and desulfidation, respectively. TGA data also indicate that the natrojarosite structure collapses at 446.6 °C, resulting in the formation of NaFe(SO4)2 and minor hematite. The decomposition products of NaFe(SO4) are hematite and Na,2SO4. Powder X-ray diffraction (XRD) analyses show that the jarosite-group minerals have mean unit-cell parameters of a=7.315 ä and c=016.598 ä. XRD and EMP data support the view that substitutions of Na for K in the A site and full Fe occupancy in the B site can considerably decrease the unit-cell parameter c, but only slightly increase a. The results from this study suggest that the observed oscillatory zoning of jarosite-group minerals at Xitieshan resulted mainly from substitutions of K for Na at the A site and P for S at the X site.

  9. Mineralogical and geochemical characteristics of a serpentinite-derived laterite profile from East Sulawesi, Indonesia: Implications for the lateritization process and Ni supergene enrichment in the tropical rainforest

    NASA Astrophysics Data System (ADS)

    Fu, Wei; Yang, Jianwen; Yang, Mengli; Pang, Baocheng; Liu, Xijun; Niu, Hujie; Huang, Xiaorong

    2014-10-01

    To evaluate the lateritization process and supergene Ni enrichment in the tropical rainforest, a well developed laterite profile over the serpentinite in the Kolonodale area of East Sulawesi, Indonesia, has been investigated using field geology methods, mineralogical and geochemical techniques. Three lithostratigraphic horizons over the bedrock are distinguished from bottom to top: the saprolite horizon, the limonite horizon, and the ferruginous cap. In general, the profile is characterized by (1) a depth-related pH ranging from 5.56 to 8.56, with a higher value in the saprolite horizon and a lower value in the ferruginous cap, (2) a highly variable organic matter concentration from 1.11% to 4.82%, showing a increasing trend from bottom to top, (3) a progressive mineral assemblage transition from the silicate mineral dominant (mainly serpentine) to the Fe-oxyhydroxide dominant (mainly goethite), and (4) a typical laterite geochemical pattern with an increase of Fe, Al, Mn, Cr and Ti but a decrease of Mg, Ca, Na and K upward from the bedrock. The highest concentration of Ni (up to 11.53%NiO) occurs in the saprolite horizon, showing nearly 40 times richer compared to the bedrock. The mineral evolution during the lateritization process shows various paths from the primary minerals to altered minerals, which is integrally affected by the nature of the primary minerals and environmental conditions. Garnierite, as a significant ore mineral formed by the secondary precipitation processes in the study profile, is identified as a mixture of talc- and serpentine-like phases. The mass-balance calculation reveals that there are diversified elemental behaviors during the serpentinite lateritization under the rainforest conditions. In particular, Ni, as the ore-forming element in the laterite profile, is associated closely with the pH environment, organic matter concentration and mineral evolution during the lateritization process. The findings of the present study support a

  10. Peptide identification

    DOEpatents

    Jarman, Kristin H [Richland, WA; Cannon, William R [Richland, WA; Jarman, Kenneth D [Richland, WA; Heredia-Langner, Alejandro [Richland, WA

    2011-07-12

    Peptides are identified from a list of candidates using collision-induced dissociation tandem mass spectrometry data. A probabilistic model for the occurrence of spectral peaks corresponding to frequently observed partial peptide fragment ions is applied. As part of the identification procedure, a probability score is produced that indicates the likelihood of any given candidate being the correct match. The statistical significance of the score is known without necessarily having reference to the actual identity of the peptide. In one form of the invention, a genetic algorithm is applied to candidate peptides using an objective function that takes into account the number of shifted peaks appearing in the candidate spectrum relative to the test spectrum.

  11. Antimicrobial Peptides and Colitis

    PubMed Central

    Ho, Samantha; Pothoulakis, Charalabos; Koon, Hon Wai

    2013-01-01

    Antimicrobial peptides (AMPs) are important components of innate immunity. They are often expressed in response to colonic inflammation and infection. Over the last several years, the roles of several antimicrobial peptides have been explored. Gene expression of many AMPs (beta defensin HBD2-4 and cathelicidin) is induced in response to invasion of gut microbes into the mucosal barrier. Some AMPs are expressed in a constitutive manner (alpha defensin HD 5-6 and beta defensin HBD1), while others (defensin and bactericidal/permeability increasing protein BPI) are particularly associated with Inflammatory Bowel Disease (IBD) due to altered defensin expression or development of autoantibodies against Bactericidal/permeability increasing protein (BPI). Various AMPs have different spectrum and strength of antimicrobial effects. Some may play important roles in modulating the colitis (cathelicidin) while others (lactoferrin, hepcidin) may represent biomarkers of disease activity. The use of AMPs for therapeutic purposes is still at an early stage of development. A few natural AMPs were shown to be able to modulate colitis when delivered intravenously or intracolonically (cathelicidin, elafin and SLPI) in mouse colitis models. New AMPs (synthetic or artificial non-human peptides) are being developed and may represent new therapeutic approaches against colitis. This review discusses the latest research developments in the AMP field with emphasis in innate immunity and pathophysiology of colitis. PMID:22950497

  12. Inflammatory myopathies.

    PubMed

    Podell, Michael

    2002-01-01

    Inflammatory myopathies are the result of infiltration of inflammatory cells into striated muscle, with or without an association with an underlying cause. Two broad classifications are IIMs and secondary inflammatory myopathies associated with other diseases. Standard diagnostic criteria for inflammatory myopathy include the presence of weakness or loss of specific muscle group function, an increase in CK, EMG changes associated with muscle membrane instability, and histologic evidence of inflammation. Not all these criteria, however, must be present. Fresh-frozen biopsy from two proximal muscles is recommended for biopsy confirmation. IIM can either focally affect head or neck muscles or be more diffuse. MMM is an immune-mediated disease characterized by a humoral antibody produced against the unique type IIM and type I variant mvofibers of masticatory muscles of dogs, which causes inflammation and loss of function of the muscles of mastication. Idiopathic polymyositis can affect focal muscle groups (extraocular, laryngeal) or present as multifocal or diffuse involvement of skeletal muscle in the cat and dog. Familial canine DM is an inflammatory disease of the striated muscle, skin, and vasculature in young Collies, Shetland Sheepdogs (Shelties), and, rarely, Collie-crossbred dogs. Immunosuppressive therapy is the key to successful treatment. Protozoal parasitic myopathies are the most common cause of clinically relevant secondary inflammatory myopathies. The degree of systemic involvement is often the limiting factor to successful treatment. Early recognition of the clinical signs for proper diagnostic testing and institution of appropriate therapy can result in a rewarding outcome in treating inflammatory myopathies in the cat and dog.

  13. Mycobacteria Attenuate Nociceptive Responses by Formyl Peptide Receptor Triggered Opioid Peptide Release from Neutrophils

    PubMed Central

    Voigt, Philipp; Mousa, Shaaban; Stolz, Andrea; Labuz, Dominika; Schäfer, Michael; Schaefer, Michael; Stein, Christoph; Brack, Alexander

    2009-01-01

    In inflammation, pain is regulated by a balance of pro- and analgesic mediators. Analgesic mediators include opioid peptides which are secreted by neutrophils at the site of inflammation, leading to activation of opioid receptors on peripheral sensory neurons. In humans, local opioids and opioid peptides significantly downregulate postoperative as well as arthritic pain. In rats, inflammatory pain is induced by intraplantar injection of heat inactivated Mycobacterium butyricum, a component of complete Freund's adjuvant. We hypothesized that mycobacterially derived formyl peptide receptor (FPR) and/or toll like receptor (TLR) agonists could activate neutrophils, leading to opioid peptide release and inhibition of inflammatory pain. In complete Freund's adjuvant-induced inflammation, thermal and mechanical nociceptive thresholds of the paw were quantified (Hargreaves and Randall-Selitto methods, respectively). Withdrawal time to heat was decreased following systemic neutrophil depletion as well as local injection of opioid receptor antagonists or anti-opioid peptide (i.e. Met-enkephalin, β-endorphin) antibodies indicating an increase in pain. In vitro, opioid peptide release from human and rat neutrophils was measured by radioimmunoassay. Met-enkephalin release was triggered by Mycobacterium butyricum and formyl peptides but not by TLR-2 or TLR-4 agonists. Mycobacterium butyricum induced a rise in intracellular calcium as determined by FURA loading and calcium imaging. Opioid peptide release was blocked by intracellular calcium chelation as well as phosphoinositol-3-kinase inhibition. The FPR antagonists Boc-FLFLF and cyclosporine H reduced opioid peptide release in vitro and increased inflammatory pain in vivo while TLR 2/4 did not appear to be involved. In summary, mycobacteria activate FPR on neutrophils, resulting in tonic secretion of opioid peptides from neutrophils and in a decrease in inflammatory pain. Future therapeutic strategies may aim at selective FPR

  14. Hemolysis Affects C-Peptide Immunoassay.

    PubMed

    Wu, Zhi-Qi; Lu, Ju; Xu, Hua-Guo

    2016-11-01

    C-peptide is used widely as a marker of insulin secretion, and it participates in the inflammatory response and contributes to the development of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). Previous studies have reported that C-peptide measurement was unaffected by hemolysis. However, we found that hemolysis negatively affected C-peptide assay in routine laboratory practice. We further established and validated an individualized hemolysis correction equation to correct and report accurate serum C-peptide results for hemolyzed samples. We studied the effects of hemolysis on C-peptide assay by adding lysed self red blood cells (self-RBCs) to serum. An individualized correction equation was derived. Further, we evaluated the performance of this individualized correction equation by artificially hemolyzed samples. C-peptide concentration decreased with increasing degree and exposure time of hemolysis. The individualized hemolysis correction equation derived: C-Pcorr = C-Pmeas /(0.969-1.5Hbserum/plasma -5.394 ×10(-5) Time), which can correct bias in C-peptide measurement caused by hemolysis. Hemolysis negatively affects C-peptide measurement. We can correct and report accurate serum C-peptide results for a wide range of degrees of sample hemolysis by individualized hemolysis correction equation for C-peptide assay. This correction would improve diagnostic accuracy and reduce inappropriate therapeutic decisions. © 2016 Wiley Periodicals, Inc.

  15. [Inflammatory myopathies].

    PubMed

    Maurer, Britta

    2017-02-01

    Inflammatory myopathies comprise heterogeneous, often multisystemic autoimmune diseases with muscle involvement as a common feature. The prognosis largely depends on a timely diagnosis and initiation of therapy. Given the complexity of these rare diseases, when an inflammatory myopathy is suspected patients should be referred to an expert center with established algorithms for the diagnostic work-up. The differential diagnostic exclusion of myositis mimics should ideally be carried out in close collaboration with neurologists and neuropathologists. The choice of immunosuppressive treatment should primarily depend on disease severity and organ involvement but age and comorbidities also have to be taken into account.

  16. Neogene geomorphic and climatic evolution of the central San Juan Mountains, Colorado: K/Ar age and stable isotope data on supergene alunite and jarosite from the Creede mining district

    USGS Publications Warehouse

    Rye, Robert O.; Bethke, Philip M.; Lanphere, Marvin A.; Steven, Thomas A.

    2000-01-01

    K/Ar age determinations or supergene alunite and jarosite, formed during Neogene weathering of the epithermal silver and base-metal ores of the Creede mining district, have been combined with geologic evidence to estimate the timing of regional uplift of the southern Rocky Mountains and related canyon cutting. In addition, oxygen and hydrogen isotopic studies suggest climate changes in the central San Juan Mountains during the past 5 m.y. Alunite [ideally (K,Na)Al3(SO4)2(OH)6] and jarosite [ideally KFe3(SO4)2(OH)6] can be dated by K/Ar or 40Ar/39Ar techniques and both contain OH and SO4 sites that enable four stable isotope analyses (δD, δ18OOH, and δ34S) to be made. This supergene alunite and jarosite formed by weathering of sulfide-rich ore bodies may record the evolution of the chemical and hydrologic processes affecting ancient oxidized acid ground water, as well as details of climate history and geomorphic evolution. Fine-grained (1-10 μm) supergene alunite and jarosite occur in minor fractures in the upper, oxidized parts of the 25 Ma sulfide-bearing veins of the Creede mining district, and jarosite also occurs in adjacent oxidized Ag-bearing clastic sediments. K/Ar ages for alunite range from 4.8 to 3.1 Ma, and for jarosite range from 2.6 to 0.9 Ma. The δD values for alunite and jarosite show opposite correlations with elevation, and values for jarosite correlate with age. Calculated δDH2O values of alunite fluids approach but are larger than those of present-day meteoric water. Calculated δDH2O values for jarosite fluids are more variable; the values of the youngest jarosites are lowest and are similar to those of present-day meteoric water in the district. The narrow δD-δ18OSO4 values of alunites reflects oxidation of sulfide below the water table. The greater range in these values for jarosites reflects oxidation of sulfide under vadose conditions. The ages of alunite mark the position of the paleo-water table at the end of a period of moderate

  17. Cysteine-containing peptides having antioxidant properties

    DOEpatents

    Bielicki, John K.

    2009-10-13

    Cysteine containing amphipathic alpha helices of the exchangeable apolipoproteins, as exemplified by apolipoprotein (apo) A-I.sub.Milano (R173C) and apoA-I.sub.Paris, (R151C) were found to exhibit potent antioxidant activity on phospholipid surfaces. The addition of a free thiol, at the hydrophobic/hydrophilic interface of an amphipathic alpha helix of synthetic peptides that mimic HDL-related proteins, imparts a unique antioxidant activity to these peptides which inhibits lipid peroxidation and protects phospholipids from water-soluble free radical initiators. These peptides can be used as therapeutic agents to combat cardiovascular disease, ischemia, bone disease and other inflammatory related diseases.

  18. Cysteine-containing peptides having antioxidant properties

    DOEpatents

    Bielicki, John K.

    2008-10-21

    Cysteine containing amphipathic alpha helices of the exchangeable apolipoproteins, as exemplified by apolipoprotein (apo) A-I.sub.Milano (R173C) and apoA-I.sub.Paris, (R151C) were found to exhibit potent antioxidant activity on phospholipid surfaces. The addition of a free thiol, at the hydrophobic/hydrophilic interface of an amphipathic alpha helix of synthetic peptides that mimic HDL-related proteins, imparts a unique antioxidant activity to these peptides which inhibits lipid peroxidation and protects phospholipids from water-soluble free radical initiators. These peptides can be used as therapeutic agents to combat cardiovascular disease, ischemia, bone disease and other inflammatory related diseases.

  19. Antimicrobial Peptides

    PubMed Central

    Bahar, Ali Adem; Ren, Dacheng

    2013-01-01

    The rapid increase in drug-resistant infections has presented a serious challenge to antimicrobial therapies. The failure of the most potent antibiotics to kill “superbugs” emphasizes the urgent need to develop other control agents. Here we review the history and new development of antimicrobial peptides (AMPs), a growing class of natural and synthetic peptides with a wide spectrum of targets including viruses, bacteria, fungi, and parasites. We summarize the major types of AMPs, their modes of action, and the common mechanisms of AMP resistance. In addition, we discuss the principles for designing effective AMPs and the potential of using AMPs to control biofilms (multicellular structures of bacteria embedded in extracellular matrixes) and persister cells (dormant phenotypic variants of bacterial cells that are highly tolerant to antibiotics). PMID:24287494

  20. Inflammatory cytokines.

    PubMed

    Cerami, A

    1992-01-01

    The immune system produces cytokines and other humoral factors to protect the host when threatened by inflammatory agents, microbial invasion, or injury. In some cases this complex defense network successfully restores normal homeostasis, but at other times the overproduction of immunoregulatory mediators may actually prove deleterious to the host. Some examples of immune system-mediated injury have been extensively investigated including anaphylactic shock, autoimmune disease, and immune complex disorders. More recently it has become clear that the cytokine cachectin/tumor necrosis factor (TNF) occupies a key role in the pathophysiology associated with diverse inflammatory states and other serious illnesses including septic shock and cachexia. For example, when cachectin/TNF is produced by resident macrophages during early microbial infection, it mediates an inflammatory response that may alienate and repel the attacking organisms. If the infection spreads, however, the subsequent release of large quantities of cachectin/TNF into the circulation may be catastrophic and trigger a state of lethal shock. These toxic effects occur by direct action of TNF on host cells and by the interaction with a cascade of other endogenous mediators including interleukin-1 and interferon-gamma. The biology of cachectin/TNF will be reviewed, along with the potential for modulating the effects of this pluripotent molecule in a variety of pathologic states.

  1. Anti-inflammatory actions of acupuncture.

    PubMed Central

    Zijlstra, Freek J; van den Berg-de Lange, Ineke; Huygen, Frank J P M; Klein, Jan

    2003-01-01

    Acupuncture has a beneficial effect when treating many diseases and painful conditions, and therefore is thought to be useful as a complementary therapy or to replace generally accepted pharmacological intervention. The attributive effect of acupuncture has been investigated in inflammatory diseases, including asthma, rhinitis, inflammatory bowel disease, rheumatoid arthritis, epicondylitis, complex regional pain syndrome type 1 and vasculitis. Large randomised trials demonstrating the immediate and sustained effect of acupuncture are missing. Mechanisms underlying the ascribed immunosuppressive actions of acupuncture are reviewed in this communication. The acupuncture-controlled release of neuropeptides from nerve endings and subsequent vasodilative and anti-inflammatory effects through calcitonine gene-related peptide is hypothesised. The complex interactions with substance P, the analgesic contribution of beta-endorphin and the balance between cell-specific pro-inflammatory and anti-inflammatory cytokines tumour necrosis factor-alpha and interleukin-10 are discussed. PMID:12775355

  2. Inflammatory Bowel Disease

    MedlinePlus

    ... work? How does inflammatory bowel disease interfere with digestion? Who gets inflammatory bowel disease? How is inflammatory ... top How does inflammatory bowel disease interfere with digestion? When the small intestine becomes inflamed, as in ...

  3. Staphylococcus aureus Infection of Epidermal Keratinocytes Promotes Expression of Innate Antimicrobial Peptides

    PubMed Central

    Menzies, Barbara E.; Kenoyer, Aimee

    2005-01-01

    Keratinocytes upregulate expression of endogenous antimicrobial peptides in response to inflammatory stimuli. We show that both viable and heat-inactivated Staphylococcus aureus and lipoteichoic acid differentially alter expression of these peptides upon contact with human keratinocytes. The findings indicate a diversity of staphylococcal factors involved in upregulation of antimicrobial peptide expression in cutaneous epithelia. PMID:16041048

  4. Sulforaphane exerts its anti-inflammatory effect against amyloid-β peptide via STAT-1 dephosphorylation and activation of Nrf2/HO-1 cascade in human THP-1 macrophages.

    PubMed

    An, Ye Won; Jhang, Kyoung A; Woo, So-Youn; Kang, Jihee Lee; Chong, Young Hae

    2016-02-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide, accounting for most cases of dementia in elderly individuals, and effective therapies are still lacking. This study was designed to investigate the anti-inflammatory properties of sulforaphane against Aβ1-42 monomers in human THP-1 microglia-like cells. The results showed that sulforaphane preferentially inhibited cathepsin B- and caspase-1-dependent NLRP3 inflammasome activation induced by mostly Aβ1-42 monomers, an effect that potently reduced excessive secretion of the proinflammatory cytokine interleukin-1β (IL-1β). Subsequent mechanistic studies revealed that sulforaphane mitigated the activation of signal transducer and activator of transcription-1 induced by Aβ1-42 monomers. Sulforaphane also increased nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, which was followed by upregulation of heme-oxygenase 1 (HO-1). The anti-inflammatory effect of sulforaphane on Aβ1-42-induced IL-1β production was diminished by small interfering RNA-mediated knockdown of Nrf2 or HO-1. Moreover, sulforaphane significantly attenuated the levels of microRNA-146a, which is selectively upregulated in the temporal cortex and hippocampus of AD brains. The aforementioned effects of sulforaphane were replicated by the tyrosine kinase inhibitor, herbimycin A, and Nrf2 activator. These results indicate that signal transducer and activator of transcription-1 dephosphorylation, HO-1 and its upstream effector, Nrf2, play a pivotal role in triggering an anti-inflammatory signaling cascade of sulforaphane that results in decreases of IL-1β release and microRNA-146a production in Aβ1-42-stimulated human microglia-like cells. These findings suggest that the phytochemical sulforaphane has a potential application in AD therapeutics. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. C-Peptide Test

    MedlinePlus

    ... vital for the body to use its main energy source, glucose . Since C-peptide and insulin are produced ... these cases, C-peptide measurement is a useful alternative to testing for insulin. C-peptide measurements can ...

  6. APL-2, an altered peptide ligand derived from heat-shock protein 60, induces interleukin-10 in peripheral blood mononuclear cell derived from juvenile idiopathic arthritis patients and downregulates the inflammatory response in collagen-induced arthritis model.

    PubMed

    Lorenzo, Norailys; Cantera, Dolores; Barberá, Ariana; Alonso, Amaris; Chall, Elsy; Franco, Lourdes; Ancizar, Julio; Nuñez, Yanetsy; Altruda, Fiorella; Silengo, Lorenzo; Padrón, Gabriel; Del Carmen Dominguez, Maria

    2015-02-01

    Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases characterized by autoimmune arthritis of unknown cause with onset before age of 16 years. Methotrexate provides clinical benefits in JIA. For children who do not respond to methotrexate, treatment with anti-tumor necrosis factor (TNF)-α is an option. However, some patients do not respond or are intolerant to anti-TNF therapy. Induction of peripheral tolerance has long been considered a promising approach to the treatment of chronic autoimmune diseases. We aimed to evaluate the potentialities of two altered peptide ligands (APLs) derived from human heat-shock protein 60, an autoantigen involved in the pathogenesis of autoimmune arthritis, in JIA patients. Interferon (IFN)-γ, TNF-α and interleukin (IL)-10 levels were determined in ex vivo assays using peripheral blood mononuclear cells (PBMC) from these patients. Wild-type peptide and one of these APLs increased IFN-γ and TNF-α levels. Unlike, the other APLs (called APL2) increased the IL-10 level without affecting IFN-γ and TNF-α levels. On the other hand, APL2 induces a marked activation of T cells since it transforms cell cycle phase's distribution of CD4+ T cells from these patients. In addition, we evaluated the therapeutic effect of APL2 in collagen-induced arthritis model. Therapy with APL2 reduced arthritis scores and histological lesions in mice. This effect was associated to a decrease in TNF-α and IL-17 levels. These results indicate a therapeutic potentiality of APL2 for JIA.

  7. Inflammatory glaucoma

    PubMed Central

    Bodh, Sonam A.; Kumar, Vasu; Raina, Usha K.; Ghosh, B.; Thakar, Meenakshi

    2011-01-01

    Glaucoma is seen in about 20% of the patients with uveitis. Anterior uveitis may be acute, subacute, or chronic. The mechanisms by which iridocyclitis leads to obstruction of aqueous outflow include acute, usually reversible forms (e.g., accumulation of inflammatory elements in the intertrabecular spaces, edema of the trabecular lamellae, or angle closure due to ciliary body swelling) and chronic forms (e.g., scar formation or membrane overgrowth in the anterior chamber angle). Careful history and follow-up helps distinguish steroid-induced glaucoma from uveitic glaucoma. Treatment of combined iridocyclitis and glaucoma involves steroidal and nonsteroidal antiinflammatory agents and antiglaucoma drugs. However, glaucoma drugs can often have an unpredictable effect on intraocular pressure (IOP) in the setting of uveitis. Surgical intervention is required in case of medical failure. Method of Literature Search: Literature on the Medline database was searched using the PubMed interface. PMID:21713239

  8. Functions of Cationic Host Defense Peptides in Immunity

    PubMed Central

    Hemshekhar, Mahadevappa; Anaparti, Vidyanand; Mookherjee, Neeloffer

    2016-01-01

    Cationic host defense peptides are a widely distributed family of immunomodulatory molecules with antimicrobial properties. The biological functions of these peptides include the ability to influence innate and adaptive immunity for efficient resolution of infections and simultaneous modulation of inflammatory responses. This unique dual bioactivity of controlling infections and inflammation has gained substantial attention in the last three decades and consequent interest in the development of these peptide mimics as immunomodulatory therapeutic candidates. In this review, we summarize the current literature on the wide range of functions of cationic host defense peptides in the context of the mammalian immune system. PMID:27384571

  9. Antimicrobial Peptides in Human Sepsis

    PubMed Central

    Martin, Lukas; van Meegern, Anne; Doemming, Sabine; Schuerholz, Tobias

    2015-01-01

    Nearly 100 years ago, antimicrobial peptides (AMPs) were identified as an important part of innate immunity. They exist in species from bacteria to mammals and can be isolated in body fluids and on surfaces constitutively or induced by inflammation. Defensins have anti-bacterial effects against Gram-positive and Gram-negative bacteria as well as anti-viral and anti-yeast effects. Human neutrophil peptides (HNP) 1–3 and human beta-defensins (HBDs) 1–3 are some of the most important defensins in humans. Recent studies have demonstrated higher levels of HNP 1–3 and HBD-2 in sepsis. The bactericidal/permeability-increasing protein (BPI) attenuates local inflammatory response and decreases systemic toxicity of endotoxins. Moreover, BPI might reflect the severity of organ dysfunction in sepsis. Elevated plasma lactoferrin is detected in patients with organ failure. HNP 1–3, lactoferrin, BPI, and heparin-binding protein are increased in sepsis. Human lactoferrin peptide 1–11 (hLF 1–11) possesses antimicrobial activity and modulates inflammation. The recombinant form of lactoferrin [talactoferrin alpha (TLF)] has been shown to decrease mortality in critically ill patients. A phase II/III study with TLF in sepsis did not confirm this result. The growing number of multiresistant bacteria is an ongoing problem in sepsis therapy. Furthermore, antibiotics are known to promote the liberation of pro-inflammatory cell components and thus augment the severity of sepsis. Compared to antibiotics, AMPs kill bacteria but also neutralize pathogenic factors such as lipopolysaccharide. The obstacle to applying naturally occurring AMPs is their high nephro- and neurotoxicity. Therefore, the challenge is to develop peptides to treat septic patients effectively without causing harm. This overview focuses on natural and synthetic AMPs in human and experimental sepsis and their potential to provide significant improvements in the treatment of critically ill with severe infections

  10. Differential peptide binding to CD40 evokes counteractive responses.

    PubMed

    Khan, Srijit; Alonso-Sarduy, Livan; Alonso, Livan; Roduit, Charles; Bandyopadhyay, Syamdas; Singh, Shailza; Saha, Shipra; Tacchini-Cottier, Fabienne; Roy, Somenath; Dietler, Giovanni; Kasas, Sandor; Das, Pradeep; Krishnasastry, M V; Saha, Bhaskar

    2012-05-01

    The antigen-presenting cell–expressed CD40 is implied in the regulation of counteractive immune responses such as induction of pro-inflammatory and anti-inflammatory cytokines interleukin (IL)–12 and IL-10, respectively. The mechanism of this duality in CD40 function remains unknown. Here, we investigated whether such duality depends on ligand binding. Based on CD40 binding, we identifed two dodecameric peptides, peptide-7 and peptide-19, from the phage peptide library. Peptide-7 induces IL-10 and increases Leishmania donovani infection in macrophages, whereas peptide-19 induces IL-12 and reduces L. donovani infection. CD40-peptide interaction analyses by surface plasmon resonance and atomic force microscopy suggest that the functional differences are not associated with the studied interaction parameters. The molecular dynamic simulation of the CD40-peptides interaction suggests that these two peptides bind to two different places on CD40. Thus, we suggest for the first time that differential binding of the ligands imparts functional duality to CD40.

  11. [SYNTHETIC PEPTIDE VACCINES].

    PubMed

    Sergeyev, O V; Barinsky, I F

    2016-01-01

    An update on the development and trials of synthetic peptide vaccines is reviewed. The review considers the successful examples of specific protection as a result of immunization with synthetic peptides using various protocols. The importance of conformation for the immunogenicity of the peptide is pointed out. An alternative strategy of the protection of the organism against the infection using synthetic peptides is suggested.

  12. BT cationic peptides: small peptides that modulate innate immune responses of chicken heterophils and monocytes.

    PubMed

    Kogut, Michael H; Genovese, Kenneth J; He, Haiqi; Swaggerty, Christina L; Jiang, Yi Wei

    2012-01-15

    with inflammatory agonists. BT peptides primed both heterophils and monocytes for an increased oxidative burst and up-regulation in transcription of the pro-inflammatory cytokines IL-1β and IL-6 and inflammatory chemokines CXCLi1 and CXCLi2 induced by inflammatory agonists. In addition, BT peptides induced a rapid (10min) phosphorylation and activation of the extracellular signal-regulated kinase (ERK1/2) and p38 kinase pathways in primary chicken heterophils. Taken together, we conclude that BT peptides, acting through MAPK pathways, enhance leukocyte functional and pro-inflammatory cytokine and chemokine gene transcription activities. These small cationic peptides may prove useful as immune modulators in neonatal poultry.

  13. Infrared and Raman spectroscopic characterizations on new Fe sulphoarsenate hilarionite (Fe2((III))(SO4)(AsO4)(OH)·6H2O): Implications for arsenic mineralogy in supergene environment of mine area.

    PubMed

    Liu, Jing; He, LiLe; Dong, Faqin; Frost, Ray L

    2017-01-05

    Hilarionite (Fe2 (SO4)(AsO4)(OH)·6H2O) is a new Fe sulphoarsenates mineral, which recently is found in the famous Lavrion ore district, Atliki Prefecture, Greece. The spectroscopic study of hilarionite enriches the data of arsenic mineralogy in supergene environment of a mine area. The infrared and Raman means are used to characterize the molecular structure of this mineral. The IR bands at 875 and 905cm(-1) are assigned to the antisymmetric stretching vibrations of AsO4(3-). The IR bands at 1021, 1086 and 1136cm(-1) correspond to the possible antisymmetric and symmetric stretching vibrations of SO4(2-). The Raman bands at 807, 843 and 875cm(-1) clearly show that arsenate components in the mineral structure, which are assigned to the symmetric stretching vibrations (ν1) of AsO4(3-) (807 and 843cm(-1)) and the antisymmetric vibration (ν3) (875cm(-1)). IR bands provide more sulfate information than Raman, which can be used as the basis to distinguish hilarionite from kaňkite. The powder XRD data shows that hilarionite has obvious differences with the mineral structure of kaňkite. The thermoanalysis and SEM-EDX results show that hilarionite has more sulfate than arsenate.

  14. Infrared and Raman spectroscopic characterizations on new Fe sulphoarsenate hilarionite (Fe2(III)(SO4)(AsO4)(OH)·6H2O): Implications for arsenic mineralogy in supergene environment of mine area

    NASA Astrophysics Data System (ADS)

    Liu, Jing; He, LiLe; Dong, Faqin; Frost, Ray L.

    2017-01-01

    Hilarionite (Fe2 (SO4)(AsO4)(OH)·6H2O) is a new Fe sulphoarsenates mineral, which recently is found in the famous Lavrion ore district, Atliki Prefecture, Greece. The spectroscopic study of hilarionite enriches the data of arsenic mineralogy in supergene environment of a mine area. The infrared and Raman means are used to characterize the molecular structure of this mineral. The IR bands at 875 and 905 cm- 1 are assigned to the antisymmetric stretching vibrations of AsO43 -. The IR bands at 1021, 1086 and 1136 cm- 1 correspond to the possible antisymmetric and symmetric stretching vibrations of SO42 -. The Raman bands at 807, 843 and 875 cm- 1 clearly show that arsenate components in the mineral structure, which are assigned to the symmetric stretching vibrations (ν1) of AsO43 - (807 and 843 cm- 1) and the antisymmetric vibration (ν3) (875 cm- 1). IR bands provide more sulfate information than Raman, which can be used as the basis to distinguish hilarionite from kaňkite. The powder XRD data shows that hilarionite has obvious differences with the mineral structure of kaňkite. The thermoanalysis and SEM-EDX results show that hilarionite has more sulfate than arsenate.

  15. Peptide Mimetics of Apolipoproteins Improve HDL Function

    PubMed Central

    Navab, Mohamad; Anantharamaiah, G. M.; Reddy, Srinivasa T.; Van Lenten, Brian J.; Buga, Georgette M.; Fogelman, Alan M.

    2007-01-01

    Over the past decade evidence has accumulated that suggests that the anti-inflammatory properties of HDL may be at least as important as the levels of HDL-cholesterol. The recent failure of the torcetrapib clinical trails has highlighted the potential differences between HDL-cholesterol levels and HDL function. Agents to improve HDL function including HDL anti-inflammatory properties provide a new therapeutic strategy for ameliorating atherosclerosis and other chronic inflammatory conditions related to dyslipidemia. Seeking guidance from the structure of the apolipoproteins of the plasma lipoproteins has allowed the creation of a series of polypeptides that have interesting functionality with therapeutic implications. In animal models of atherosclerosis, peptide mimetics of apolipoproteins have been shown to improve the anti-inflammatory properties of HDL, significantly reduce lesions and improve vascular inflammation and function without necessarily altering HDL-cholesterol levels. Some of these are now entering the clinical arena as interventions in pharmacologic and pharmacodynamic studies. PMID:18449337

  16. Regulatory Peptides in Plants.

    PubMed

    Vanyushin, B F; Ashapkin, V V; Aleksandrushkina, N I

    2017-02-01

    Many different peptides regulating cell differentiation, growth, and development are found in plants. Peptides participate in regulation of plant ontogenesis starting from pollination, pollen tube growth, and the very early stages of embryogenesis, including formation of embryo and endosperm. They direct differentiation of meristematic stem cells, formation of tissues and individual organs, take part in regulation of aging, fruit maturation, and abscission of plant parts associated with apoptosis. Biological activity of peptides is observed at very low concentrations, and it has mainly signal nature and hormonal character. "Mature" peptides appear mainly due to processing of protein precursors with (or without) additional enzymatic modifications. Plant peptides differ in origin, structure, and functional properties. Their specific action is due to binding with respective receptors and interactions with various proteins and other factors. Peptides can also regulate physiological functions by direct peptide-protein interactions. Peptide action is coordinated with the action of known phytohormones (auxins, cytokinins, and others); thus, peptides control phytohormonal signal pathways.

  17. TRH-like peptides.

    PubMed

    Bílek, R; Bičíková, M; Šafařík, L

    2011-01-01

    TRH-like peptides are characterized by substitution of basic amino acid histidine (related to authentic TRH) with neutral or acidic amino acid, like glutamic acid, phenylalanine, glutamine, tyrosine, leucin, valin, aspartic acid and asparagine. The presence of extrahypothalamic TRH-like peptides was reported in peripheral tissues including gastrointestinal tract, placenta, neural tissues, male reproductive system and certain endocrine tissues. Work deals with the biological function of TRH-like peptides in different parts of organisms where various mechanisms may serve for realisation of biological function of TRH-like peptides as negative feedback to the pituitary exerted by the TRH-like peptides, the role of pEEPam such as fertilization-promoting peptide, the mechanism influencing the proliferative ability of prostatic tissues, the neuroprotective and antidepressant function of TRH-like peptides in brain and the regulation of thyroid status by TRH-like peptides.

  18. Peptide Antimicrobial Agents

    PubMed Central

    Jenssen, Håvard; Hamill, Pamela; Hancock, Robert E. W.

    2006-01-01

    Antimicrobial host defense peptides are produced by all complex organisms as well as some microbes and have diverse and complex antimicrobial activities. Collectively these peptides demonstrate a broad range of antiviral and antibacterial activities and modes of action, and it is important to distinguish between direct microbicidal and indirect activities against such pathogens. The structural requirements of peptides for antiviral and antibacterial activities are evaluated in light of the diverse set of primary and secondary structures described for host defense peptides. Peptides with antifungal and antiparasitic activities are discussed in less detail, although the broad-spectrum activities of such peptides indicate that they are important host defense molecules. Knowledge regarding the relationship between peptide structure and function as well as their mechanism of action is being applied in the design of antimicrobial peptide variants as potential novel therapeutic agents. PMID:16847082

  19. Food-Derived Bioactive Peptides on Inflammation and Oxidative Stress

    PubMed Central

    2014-01-01

    Chronic diseases such as atherosclerosis and cancer are now the leading causes of morbidity and mortality worldwide. Inflammatory processes and oxidative stress underlie the pathogenesis of these pathological conditions. Bioactive peptides derived from food proteins have been evaluated for various beneficial effects, including anti-inflammatory and antioxidant properties. In this review, we summarize the roles of various food-derived bioactive peptides in inflammation and oxidative stress and discuss the potential benefits and limitations of using these compounds against the burden of chronic diseases. PMID:24527452

  20. PH dependent adhesive peptides

    DOEpatents

    Tomich, John; Iwamoto, Takeo; Shen, Xinchun; Sun, Xiuzhi Susan

    2010-06-29

    A novel peptide adhesive motif is described that requires no receptor or cross-links to achieve maximal adhesive strength. Several peptides with different degrees of adhesive strength have been designed and synthesized using solid phase chemistries. All peptides contain a common hydrophobic core sequence flanked by positively or negatively charged amino acids sequences.

  1. Antimicrobial Peptides in 2014

    PubMed Central

    Wang, Guangshun; Mishra, Biswajit; Lau, Kyle; Lushnikova, Tamara; Golla, Radha; Wang, Xiuqing

    2015-01-01

    This article highlights new members, novel mechanisms of action, new functions, and interesting applications of antimicrobial peptides reported in 2014. As of December 2014, over 100 new peptides were registered into the Antimicrobial Peptide Database, increasing the total number of entries to 2493. Unique antimicrobial peptides have been identified from marine bacteria, fungi, and plants. Environmental conditions clearly influence peptide activity or function. Human α-defensin HD-6 is only antimicrobial under reduced conditions. The pH-dependent oligomerization of human cathelicidin LL-37 is linked to double-stranded RNA delivery to endosomes, where the acidic pH triggers the dissociation of the peptide aggregate to release its cargo. Proline-rich peptides, previously known to bind to heat shock proteins, are shown to inhibit protein synthesis. A model antimicrobial peptide is demonstrated to have multiple hits on bacteria, including surface protein delocalization. While cell surface modification to decrease cationic peptide binding is a recognized resistance mechanism for pathogenic bacteria, it is also used as a survival strategy for commensal bacteria. The year 2014 also witnessed continued efforts in exploiting potential applications of antimicrobial peptides. We highlight 3D structure-based design of peptide antimicrobials and vaccines, surface coating, delivery systems, and microbial detection devices involving antimicrobial peptides. The 2014 results also support that combination therapy is preferred over monotherapy in treating biofilms. PMID:25806720

  2. Effect of Rumalon (glycosaminoglycan-peptide) on the articular tissue.

    PubMed

    Skrivánková, B; Julis, I; Podrazký, V; Trnavský, K

    1993-01-01

    The effect of glycosaminoglycan-peptide complex (GPC) (Rumalon, made by Robapharm, Switzerland) on cells of the inflammatory periarticular infiltrate and on the articular chondrocytes was studied in experimentally induced papain arthropathy by means of image cytometry and biochemistry. The GPC therapy exhibited some antiinflammatory effect as documented by the reduction of DNA proliferative activity in the inflammatory infiltrate and lowered the activity of hydrolytic enzymes and enzyme inhibitors detected in chondrocytes.

  3. A potential peptide pathway from viruses to oral lichen planus.

    PubMed

    Lucchese, Alberta

    2015-06-01

    Oral lichen planus is an idiopathic inflammatory disease of oral mucous membranes, characterized by an autoimmune epidermis attack by T cells. It remains unknown, however, how such aggressive T cells are activated in vivo to cause epidermal damage. This study analyzes the relationship at the peptide level between viruses and oral lichen planus disease. Four potentially immunogenic peptides (SSSSSSS, QEQLEKA, LLLLLLA, and MLSGNAG) are found to be shared between HCV, EBV, HHV-7, HSV-1, and CMV and three human proteins (namely pinin, desmoglein-3, and plectin). The described peptide sharing might be of help in deciphering the still unexplained immunopathogenic pathway that leads to oral lichen planus. © 2015 Wiley Periodicals, Inc.

  4. Bioactive peptides derived from egg proteins: A review.

    PubMed

    Liu, Ya-Fei; Oey, Indrawati; Bremer, Phil; Carne, Alan; Silcock, Pat

    2017-06-13

    Egg proteins have various functional and biological activities which make them potential precursor proteins for bioactive peptide production. Simulated in vitro gastrointestinal digestion and enzymatic hydrolysis using non-gastrointestinal proteases have been used as tools to produce these peptides. Bioactive peptides derived from egg proteins are reported to display various biological activities, including angiotensin I-converting enzyme (ACE) inhibitory (antihypertensive), antioxidant, antimicrobial, anti-inflammatory, antidiabetic and iron-/calcium-binding activities. More importantly, simulated in vitro gastrointestinal digestion has indicated that consumption of egg proteins has physiological benefits due to the release of such multifunctional peptides. This review encompasses studies reported to date on the bioactive peptide production from egg proteins.

  5. Peptide signaling in Hydra.

    PubMed

    Fujisawa, Toshitaka; Hayakawa, Eisuke

    2012-01-01

    Peptides play a number of crucial roles as signaling molecules in metazoans. In order to elaborate a more complete picture of the roles played by peptides in a single organism, we launched the "Hydra Peptide Project". For this project, we used Hydra magnipapillata, a species belonging to Cnidaria, one of the most basal metazoan phyla, and using a peptidomic approach, we systematically identified a number of peptide signaling molecules, their encoding genes and their functions. In this article, we report the peptides isolated from Hydra and other cnidarians, as well as their synthesis, processing and release from the cells to the target. Possible peptide signaling pathways are overviewed and finally we discuss the evolution of the peptide signaling system.

  6. A switchable stapled peptide.

    PubMed

    Kalistratova, Aleksandra; Legrand, Baptiste; Verdié, Pascal; Naydenova, Emilia; Amblard, Muriel; Martinez, Jean; Subra, Gilles

    2016-03-01

    The O-N acyl transfer reaction has gained significant popularity in peptide and medicinal chemistry. This reaction has been successfully applied to the synthesis of difficult sequence-containing peptides, cyclic peptides, epimerization-free fragment coupling and more recently, to switchable peptide polymers. Herein, we describe a related strategy to facilitate the synthesis and purification of a hydrophobic stapled peptide. The staple consists of a serine linked through an amide bond formed from its carboxylic acid function and the side chain amino group of diaminopropionic acid and through an ester bond formed from its amino group and the side chain carboxylic acid function of aspartic acid. The α-amino group of serine was protonated during purification. Interestingly, when the peptide was placed at physiological pH, the free amino group initiated the O-N shift reducing the staple length by one atom, leading to a more hydrophobic stapled peptide.

  7. Investigation on cellular uptake and pharmacodynamics of DOCK2-inhibitory peptides conjugated with cell-penetrating peptides.

    PubMed

    Adachi, Yusuke; Sakamoto, Kotaro; Umemoto, Tadashi; Fukuda, Yasunori; Tani, Akiyoshi; Asami, Taiji

    2017-04-01

    Protein-protein interaction between dedicator of cytokinesis 2 (DOCK2) and Ras-related C3 botulinum toxin substrate 1 (Rac1) is an attractive intracellular target for transplant rejection and inflammatory diseases. Recently, DOCK2-selective inhibitory peptides have been discovered, and conjugation with oligoarginine cell-penetrating peptide (CPP) improved inhibitory activity in a cell migration assay. Although a number of CPPs have been reported, oligoarginine was only one example introduced to the inhibitory peptides. In this study, we aimed to confirm the feasibility of CPP-conjugation approach for DOCK2-inhibitory peptides, and select preferable sequences as CPP moiety. First, we evaluated cell permeability of thirteen known CPPs and partial sequences of influenza A viral protein PB1-F2 using an internalization assay system based on luciferin-luciferase reaction, and then selected four CPPs with efficient cellular uptake. Among four conjugates of these CPPs and a DOCK2-inhibitory peptide, the inhibitory activity of a novel CPP, PB1-F2 fragment 5 (PF5), conjugate was comparable to oligoarginine conjugate and higher than that of the non-conjugated peptide. Finally, internalization assay revealed that oligoarginine and PF5 increased the cellular uptake of inhibitory peptides to the same extent. Hence, we demonstrated that CPP-conjugation approach is applicable to the development of novel anti-inflammatory drugs based on DOCK2 inhibition by investigating both cellular uptake and bioactivity.

  8. Cell Penetrating Peptides and Cationic Antibacterial Peptides

    PubMed Central

    Rodriguez Plaza, Jonathan G.; Morales-Nava, Rosmarbel; Diener, Christian; Schreiber, Gabriele; Gonzalez, Zyanya D.; Lara Ortiz, Maria Teresa; Ortega Blake, Ivan; Pantoja, Omar; Volkmer, Rudolf; Klipp, Edda; Herrmann, Andreas; Del Rio, Gabriel

    2014-01-01

    Cell penetrating peptides (CPP) and cationic antibacterial peptides (CAP) have similar physicochemical properties and yet it is not understood how such similar peptides display different activities. To address this question, we used Iztli peptide 1 (IP-1) because it has both CPP and CAP activities. Combining experimental and computational modeling of the internalization of IP-1, we show it is not internalized by receptor-mediated endocytosis, yet it permeates into many different cell types, including fungi and human cells. We also show that IP-1 makes pores in the presence of high electrical potential at the membrane, such as those found in bacteria and mitochondria. These results provide the basis to understand the functional redundancy of CPPs and CAPs. PMID:24706763

  9. Melanocyte stimulating hormone peptides inhibit TNF-alpha signaling in human dermal fibroblast cells.

    PubMed

    Hill, R P; MacNeil, S; Haycock, J W

    2006-02-01

    Alpha-melanocyte stimulating hormone (alpha-MSH) has been identified as a potent anti-inflammatory in various tissues including the skin. It has previously been shown in skin cell keratinocytes and melanocytes/melanoma cells that MSH peptides inhibit TNF-alpha stimulated NF-kappaB activity and intercellular adhesion molecule-1 (ICAM-1) upregulation. However, the precise anti-inflammatory role of MSH peptides in dermal fibroblasts is unclear. Some studies report on pro-inflammatory responses, while others on anti-inflammatory responses. The present study confirms MC1R expression in cultured human dermal fibroblasts and reports that the MSH peptides alpha-MSH and KP(-D-)V inhibit TNF-alpha stimulated NF-kappaB activity and ICAM-1 upregulation, consistent with an anti-inflammatory role. However, involvement of IkappaB-alpha regulation by either peptide was not confirmed, supporting a mechanism independent of the NF-kappaB inhibitor. In conclusion, alpha-MSH and KP(-D-)V peptides have an anti-inflammatory action on dermal fibroblast signaling by inhibiting the pro-inflammatory activity of TNF-alpha in vitro.

  10. Plant peptide hormone signalling.

    PubMed

    Motomitsu, Ayane; Sawa, Shinichiro; Ishida, Takashi

    2015-01-01

    The ligand-receptor-based cell-to-cell communication system is one of the most important molecular bases for the establishment of complex multicellular organisms. Plants have evolved highly complex intercellular communication systems. Historical studies have identified several molecules, designated phytohormones, that function in these processes. Recent advances in molecular biological analyses have identified phytohormone receptors and signalling mediators, and have led to the discovery of numerous peptide-based signalling molecules. Subsequent analyses have revealed the involvement in and contribution of these peptides to multiple aspects of the plant life cycle, including development and environmental responses, similar to the functions of canonical phytohormones. On the basis of this knowledge, the view that these peptide hormones are pivotal regulators in plants is becoming increasingly accepted. Peptide hormones are transcribed from the genome and translated into peptides. However, these peptides generally undergo further post-translational modifications to enable them to exert their function. Peptide hormones are expressed in and secreted from specific cells or tissues. Apoplastic peptides are perceived by specialized receptors that are located at the surface of target cells. Peptide hormone-receptor complexes activate intracellular signalling through downstream molecules, including kinases and transcription factors, which then trigger cellular events. In this chapter we provide a comprehensive summary of the biological functions of peptide hormones, focusing on how they mature and the ways in which they modulate plant functions.

  11. Urinary proteomics can define distinct diagnostic inflammatory arthritis subgroups

    PubMed Central

    Siebert, Stefan; Porter, Duncan; Paterson, Caron; Hampson, Rosie; Gaya, Daniel; Latosinska, Agnieszka; Mischak, Harald; Schanstra, Joost; Mullen, William; McInnes, Iain

    2017-01-01

    Current diagnostic tests applied to inflammatory arthritis lack the necessary specificity to appropriately categorise patients. There is a need for novel approaches to classify patients with these conditions. Herein we explored whether urinary proteomic biomarkers specific for different forms of arthritis (rheumatoid arthritis (RA), psoriatic arthritis (PsA), osteoarthritis (OA)) or chronic inflammatory conditions (inflammatory bowel disease (IBD)) can be identified. Fifty subjects per group with RA, PsA, OA or IBD and 50 healthy controls were included in the study. Two-thirds of these populations were randomly selected to serve as a training set, while the remaining one-third was reserved for validation. Sequential comparison of one group to the other four enabled identification of multiple urinary peptides significantly associated with discrete pathological conditions. Classifiers for the five groups were developed and subsequently tested blind in the validation test set. Upon unblinding, the classifiers demonstrated excellent performance, with an area under the curve between 0.90 and 0.97 per group. Identification of the peptide markers pointed to dysregulation of collagen synthesis and inflammation, but also novel inflammatory markers. We conclude that urinary peptide signatures can reliably differentiate between chronic arthropathies and inflammatory conditions with discrete pathogenesis. PMID:28091549

  12. Honokiol suppresses formyl peptide-induced human neutrophil activation by blocking formyl peptide receptor 1.

    PubMed

    Liu, Fu-Chao; Yu, Huang-Ping; Syu, Yu-Ting; Fang, Jia-You; Lin, Chwan-Fwu; Chang, Shih-Hsin; Lee, Yen-Tung; Hwang, Tsong-Long

    2017-07-27

    Formyl peptide receptor 1 (FPR1) mediates bacterial and mitochondrial N-formyl peptides-induced neutrophil activation. Therefore, FPR1 is an important therapeutic target for drugs to treat septic or sterile inflammatory diseases. Honokiol, a major bioactive compound of Magnoliaceae plants, possesses several anti-inflammatory activities. Here, we show that honokiol exhibits an inhibitory effect on FPR1 binding in human neutrophils. Honokiol inhibited superoxide anion generation, reactive oxygen species formation, and elastase release in bacterial or mitochondrial N-formyl peptides (FPR1 agonists)-activated human neutrophils. Adhesion of FPR1-induced human neutrophils to cerebral endothelial cells was also reduced by honokiol. The receptor-binding results revealed that honokiol repressed FPR1-specific ligand N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein binding to FPR1 in human neutrophils, neutrophil-like THP-1 cells, and hFPR1-transfected HEK293 cells. However, honokiol did not inhibit FPR2-specific ligand binding to FPR2 in human neutrophils. Furthermore, honokiol inhibited FPR1 agonist-induced calcium mobilization as well as phosphorylation of p38 MAPK, ERK, and JNK in human neutrophils. In conclusion, our data demonstrate that honokiol may have therapeutic potential for treating FPR1-mediated inflammatory diseases.

  13. Antimicrobial Peptides in Reptiles

    PubMed Central

    van Hoek, Monique L.

    2014-01-01

    Reptiles are among the oldest known amniotes and are highly diverse in their morphology and ecological niches. These animals have an evolutionarily ancient innate-immune system that is of great interest to scientists trying to identify new and useful antimicrobial peptides. Significant work in the last decade in the fields of biochemistry, proteomics and genomics has begun to reveal the complexity of reptilian antimicrobial peptides. Here, the current knowledge about antimicrobial peptides in reptiles is reviewed, with specific examples in each of the four orders: Testudines (turtles and tortosises), Sphenodontia (tuataras), Squamata (snakes and lizards), and Crocodilia (crocodilans). Examples are presented of the major classes of antimicrobial peptides expressed by reptiles including defensins, cathelicidins, liver-expressed peptides (hepcidin and LEAP-2), lysozyme, crotamine, and others. Some of these peptides have been identified and tested for their antibacterial or antiviral activity; others are only predicted as possible genes from genomic sequencing. Bioinformatic analysis of the reptile genomes is presented, revealing many predicted candidate antimicrobial peptides genes across this diverse class. The study of how these ancient creatures use antimicrobial peptides within their innate immune systems may reveal new understandings of our mammalian innate immune system and may also provide new and powerful antimicrobial peptides as scaffolds for potential therapeutic development. PMID:24918867

  14. Polycyclic peptide therapeutics.

    PubMed

    Baeriswyl, Vanessa; Heinis, Christian

    2013-03-01

    Owing to their excellent binding properties, high stability, and low off-target toxicity, polycyclic peptides are an attractive molecule format for the development of therapeutics. Currently, only a handful of polycyclic peptides are used in the clinic; examples include the antibiotic vancomycin, the anticancer drugs actinomycin D and romidepsin, and the analgesic agent ziconotide. All clinically used polycyclic peptide drugs are derived from natural sources, such as soil bacteria in the case of vancomycin, actinomycin D and romidepsin, or the venom of a fish-hunting coil snail in the case of ziconotide. Unfortunately, nature provides peptide macrocyclic ligands for only a small fraction of therapeutic targets. For the generation of ligands of targets of choice, researchers have inserted artificial binding sites into natural polycyclic peptide scaffolds, such as cystine knot proteins, using rational design or directed evolution approaches. More recently, large combinatorial libraries of genetically encoded bicyclic peptides have been generated de novo and screened by phage display. In this Minireview, the properties of existing polycyclic peptide drugs are discussed and related to their interesting molecular architectures. Furthermore, technologies that allow the development of unnatural polycyclic peptide ligands are discussed. Recent application of these technologies has generated promising results, suggesting that polycyclic peptide therapeutics could potentially be developed for a broad range of diseases. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Topical peptides as cosmeceuticals.

    PubMed

    Pai, Varadraj Vasant; Bhandari, Prasana; Shukla, Pankaj

    2017-01-01

    Peptides are known to have diverse biological roles, most prominently as signaling/regulatory molecules in a broad variety of physiological processes including defense, immunity, stress, growth, homeostasis and reproduction. These aspects have been used in the field of dermatology and cosmetology to produce short, stable and synthetic peptides for extracellular matrix synthesis, pigmentation, innate immunity and inflammation. The evolution of peptides over the century, which started with the discovery of penicillin, has now extended to their usage as cosmeceuticals in recent years. Cosmeceutical peptides may act as signal modulators of the extracellular matrix component, as structural peptides, carrier peptides and neurotransmitter function modulators. Transdermal delivery of peptides can be made more effective by penetration enhancers, chemical modification or encapsulation of peptides. The advantages of using peptides as cosmeceuticals include their involvement in many physiological functions of the skin, their selectivity, their lack of immunogenicity and absence of premarket regulatory requirements for their use. However, there are disadvantages: clinical evidence for efficacy is often weak, absorption may be poor due to low lipophilicity, high molecular weight and binding to other ingredients, and prices can be quite high.

  16. The natriuretic peptides.

    PubMed

    Baxter, Gary F

    2004-03-01

    The natriuretic peptides are a family of widely distributed, but evolutionarily conserved, polypeptide mediators that exert a range of actions throughout the body. In cardiovascular homeostasis, the endocrine roles of the cardiac-derived atrial and B-type natriuretic peptide (ANP and BNP) in regulating central fluid volume and blood pressure have been recognised for two decades. However, there is a growing realisation that natriuretic peptide actions go far beyond their volume regulating effects. These pleiotropic actions include local (autocrine/paracrine) regulatory actions of ANP and BNP within the heart, and of another natriuretic peptide, CNP, within the vessel wall. Effects on function and growth of the local tissue environment are likely to be of great importance, especially in disease states where tissue and circulating levels of ANP and BNP rise markedly. At present, the relevance of other natriuretic peptides (notably uroguanylin and DNP) to human physiology and pathology remain uncertain. Other articles in this issue of Basic Research in Cardiology review the molecular physiology of natriuretic peptide signalling, with a particular emphasis on the lessons from genetically targetted mice; the vascular activity of natriuretic peptides; the regulation and roles of natriuretic peptides in ischaemic myocardium; and the diagnostic, prognostic and therapeutic roles of natriuretic peptides in heart failure.

  17. Assaying peptide translocation by the peptide transporter TAP.

    PubMed

    Jongsma, Marlieke L M; Neefjes, Jacques

    2013-01-01

    MHC class I molecules display peptides at the cell surface that are mostly derived from cytosolic or nuclear proteins. Since peptide loading of MHC class I molecules occurs in the ER lumen, cytosolic peptides have to pass the ER membrane. The peptide transporter TAP translocates peptides over this ER membrane which is critical for successful MHC class I antigen presentation. How peptide translocation by TAP can be assayed and inhibitors of chemical or viral origin can be identified, will be described here.

  18. Neuropeptide receptors as potential drug targets in the treatment of inflammatory conditions

    PubMed Central

    Pintér, Erika; Pozsgai, Gábor; Hajna, Zsófia; Helyes, Zsuzsanna; Szolcsányi, János

    2014-01-01

    Cross-talk between the nervous, endocrine and immune systems exists via regulator molecules, such as neuropeptides, hormones and cytokines. A number of neuropeptides have been implicated in the genesis of inflammation, such as tachykinins and calcitonin gene-related peptide. Development of their receptor antagonists could be a promising approach to anti-inflammatory pharmacotherapy. Anti-inflammatory neuropeptides, such as vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, α-melanocyte-stimulating hormone, urocortin, adrenomedullin, somatostatin, cortistatin, ghrelin, galanin and opioid peptides, are also released and act on their own receptors on the neurons as well as on different inflammatory and immune cells. The aim of the present review is to summarize the most prominent data of preclinical animal studies concerning the main pharmacological effects of ligands acting on the neuropeptide receptors. Promising therapeutic impacts of these compounds as potential candidates for the development of novel types of anti-inflammatory drugs are also discussed. PMID:23432438

  19. Inflammatory myopathies and lymphoma.

    PubMed

    Stübgen, Joerg-Patrick

    2016-10-15

    The inflammatory myopathies comprise a group of immune-mediated muscle diseases. Lymphoma is a term for a variety of lymphatic system malignancies. Autoimmune diseases and lymphoproliferative malignancies share a complex bidirectional relationship. A causal relationship between inflammatory mypathies and lymphoma has not been established. The diagnosis/treatment of inflammatory myopathy usually precedes the detection/diagnosis of lymphoma. Immune system dysregulation presumably underlies the evolution of lymphoma in patients with inflammatory myopathies. Inflammatory activity with chronic B-cell activation and/or antigen stimulation is deemed the major risk factor for lymphoma in patients with autoimmunity. A "paraneoplastic" phenomenon or the effects of immunosuppressive therapy may be alternative immune-based mechanisms. In chronic lymphocytic leukemia immune system disturbance rarely results in non-hematological autoimmune disease, including inflammatory myopathies. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Bacteriocin Inducer Peptides

    USDA-ARS?s Scientific Manuscript database

    Novel peptides produced by bacteriocin-producing bacteria stimulate the production of bacteriocins in vitro. The producer bacteria are cultured in the presence of a novel inducer bacteria and a peptide having a carboxy terminal sequence of VKGLT in order to achieve an increase in bacteriocin produc...

  1. Peptide bioregulators inhibit apoptosis.

    PubMed

    Khavinson, V K; Kvetnoii, I M

    2000-12-01

    The effects of peptide bioregulators epithalon and vilon on the dynamics of irradiation-induced apoptotic death of spleen lymphocytes in rats indicate that these agents inhibit physiologically programmed cell death. The antiapoptotic effect of vilon was more pronounced, which corroborates the concept on tissue-specific effect of peptide bioregulators.

  2. Inflammatory Biomarkers and Atherosclerosis.

    PubMed

    Soeki, Takeshi; Sata, Masataka

    2016-01-01

    Atherosclerosis has been regarded as a form of chronic vascular inflammation. Numerous biomarkers associated with inflammation have been identified as novel targets to monitor atherosclerosis and cardiovascular risk. C-reactive protein (CRP) is one of the most actively studied and established inflammatory biomarkers for cardiovascular events. However, CRP response is triggered by many disorders unrelated to cardiovascular disease, which interferes with the clinical application. This review describes established and traditional inflammatory biomarkers including CRP as well as novel inflammatory biomarkers reflective of local atherosclerotic inflammation. In addition, we focus on the potential usefulness of inflammatory biomarkers in developing anti-atherosclerotic therapeutic approaches.

  3. Trefoil factors in inflammatory bowel disease

    PubMed Central

    Aamann, Luise; Vestergaard, Else Marie; Grønbæk, Henning

    2014-01-01

    Inflammatory bowel disease (IBD), which comprises ulcerative colitis and Crohn’s disease, is characterized by inflammation of the gastrointestinal tract. The trefoil factors 1, 2, and 3 (TFF1-3) are a family of peptides that play important roles in the protection and repair of epithelial surfaces, including the gastrointestinal tract. TFFs may be involved in IBD pathogenesis and are a potential treatment option. In the present review, we describe the TFF family and their potential role in IBD by summarizing the current knowledge of their expression, possible function and pharmacological role in IBD. PMID:24696606

  4. Antimicrobial Peptides from Fish

    PubMed Central

    Masso-Silva, Jorge A.; Diamond, Gill

    2014-01-01

    Antimicrobial peptides (AMPs) are found widely distributed through Nature, and participate in the innate host defense of each species. Fish are a great source of these peptides, as they express all of the major classes of AMPs, including defensins, cathelicidins, hepcidins, histone-derived peptides, and a fish-specific class of the cecropin family, called piscidins. As with other species, the fish peptides exhibit broad-spectrum antimicrobial activity, killing both fish and human pathogens. They are also immunomodulatory, and their genes are highly responsive to microbes and innate immuno-stimulatory molecules. Recent research has demonstrated that some of the unique properties of fish peptides, including their ability to act even in very high salt concentrations, make them good potential targets for development as therapeutic antimicrobials. Further, the stimulation of their gene expression by exogenous factors could be useful in preventing pathogenic microbes in aquaculture. PMID:24594555

  5. Antimicrobial Peptides, Skin Infections and Atopic Dermatitis

    PubMed Central

    Hata, Tissa R.; Gallo, Richard L.

    2008-01-01

    The innate immune system evolved over 2 billion years ago to first recognize pathogens then eradicate them. Several distinct defects in this ancient but rapidly responsive element of human immune defense account for the increased incidence of skin infections in atopics. These defects include abnormalities in the physical barrier of the epidermis, alterations in microbial pattern recognition receptors such as toll receptors and NOD, and a diminished capacity to increase the expression of antimicrobial peptides during inflammation. Several antimicrobial peptides are affected including; cathelicidin, HBD-2, and HBD-3, which are lower in lesional skin of atopics compared to other inflammatory skin diseases, and dermcidin, which is decreased in sweat. Other defects in the immune defense barrier of atopics include a relative deficiency in plasmacytoid dendritic cells. In the future, understanding the cause of these defects may allow therapeutic intervention to reduce the incidence of infection in atopic individuals and potentially decrease the severity of this disorder. PMID:18620136

  6. Characterization, Preparation, and Purification of Marine Bioactive Peptides

    PubMed Central

    Wang, Xueqin; Yu, Huahua; Xing, Ronge

    2017-01-01

    Marine bioactive peptides, as a source of unique bioactive compounds, are the focus of current research. They exert various biological roles, some of the most crucial of which are antioxidant activity, antimicrobial activity, anticancer activity, antihypertensive activity, anti-inflammatory activity, and so forth, and specific characteristics of the bioactivities are described. This review also describes various manufacturing techniques for marine bioactive peptides using organic synthesis, microwave assisted extraction, chemical hydrolysis, and enzymes hydrolysis. Finally, purification of marine bioactive peptides is described, including gel or size exclusion chromatography, ion-exchange column chromatography, and reversed-phase high-performance liquid chromatography, which are aimed at finding a fast, simple, and effective method to obtain the target peptides. PMID:28761878

  7. Integrin signaling in inflammatory and neuropathic pain in the rat.

    PubMed

    Dina, Olayinka A; Parada, Carlos A; Yeh, Jenny; Chen, Xiaojie; McCarter, Gordon C; Levine, Jon D

    2004-02-01

    Many painful conditions are associated with alterations in the extracellular matrix (ECM) of affected tissues. While several integrins, the receptors for ECM proteins, are present on sensory neurons that mediate pain, the possible role of these cell adhesion molecules in inflammatory or neuropathic pain has not been explored. We found that the intradermal injection of peptide fragments of domains of laminin and fibronectin important for adhesive signaling selectively inhibited the hyperalgesia caused by prostaglandin E2 (PGE2) and epinephrine (EPI), respectively. The block of EPI hyperalgesia was mimicked by other peptides containing the RGD integrin-binding sequence. Monoclonal antibodies (mAbs) against the alpha1 or alpha3 integrin subunits, which participate in laminin binding, selectively blocked PGE2 hyperalgesia, while a mAb against the alpha5 subunit, which participates in fibronectin binding, blocked only EPI-induced hyperalgesia. A mAb against the beta1 integrin subunit, common to receptors for both laminin and fibronectin, inhibited hyperalgesia caused by both agents, as did the knockdown of beta1 integrin expression by intrathecal injection of antisense oligodeoxynucleotides. The laminin peptide, but not the fibronectin peptides, also reversibly abolished the longer lasting inflammatory hyperalgesia induced by carrageenan. Finally, the neuropathic hyperalgesia caused by systemic administration of the cancer chemotherapy agent taxol was reversibly inhibited by antisense knockdown of beta1 integrin. These results strongly implicate specific integrins in the maintenance of inflammatory and neuropathic hyperalgesia.

  8. Intestinal immunomodulation. Role of regulative peptides and promising pharmacological activities.

    PubMed

    Motilva, V; Talero, E; Calvo, J R; Villegas, I; Alarcón-de-la-Lastra, C; Sánchez-Fidalgo, S

    2008-01-01

    About 50 peptides, and a similar number of peptide receptors, are known to be present in the gut and this amount is likely to rise significantly over the next few years. While there has been a massive research effort to define their functions and their anatomical distribution in the central nervous system (CNS), the understanding of their roles in the gut is far more limited. Classically, the physiological functions include the control of motility, fluids, electrolytes, and digestive enzymes secretion, or vascular and visceral pain function, and more recently, the role-played in cell proliferation and survival, and in immune-inflammatory responses. The term inflammatory bowel disease (IBD) that encompasses Crohn's disease and ulcerative colitis, is clearly an inflammatory disease where several mediators such as cytokines, chemokines, prostanoids, nitric oxide or free radicals, produced by infiltrating cells, play a critical role in intestine tissue alteration. Some peptides, initially known for their neuroregulative properties, have been suggested to act as endogenous immune factors, with predominant antiinflammatory effects. Based on these actions, these molecules are proposed as potential agents for the treatment of IBD and selective peptide analogs are being developed as novel therapeutic strategies for IBD patients. Patients with IBD have an increased risk for developing colorectal cancer (CRC). Up to the present time, no known genetic basis has been identified to explain CRC predisposition in these IBD. Instead, it is assumed that chronic inflammation is what causes cancer. This is supported by the fact that colon cancer risk increases with longer duration of colitis, greater anatomic extent of colitis, the concomitant presence of other inflammatory manifestations, and the fact that certain drugs used to treat inflammation, may prevent the development of CRC. However, though different regulative peptides play a beneficial role in experimental IBD, an

  9. C-peptide ameliorates kidney injury following hemorrhagic shock.

    PubMed

    Chima, Ranjit S; Maltese, Giuseppe; Lamontagne, Timberly; Piraino, Giovanna; Denenberg, Alvin; O'Connor, Michael; Zingarelli, Basilia

    2011-05-01

    Reperfusion injury following hemorrhagic shock is accompanied by the development of a systemic inflammatory state that may lead to organ failure. Insulin connecting peptide (C-peptide) has been shown to exert anti-inflammatory effects in sepsis and myocardial ischemia-reperfusion injury and to ameliorate renal dysfunction in diabetic animals. Hence, we investigated the effect of C-peptide on kidney injury after hemorrhagic shock. We hypothesized that C-peptide would exert renoprotective effects by blunting inflammation. Hemorrhagic shock was induced in male rats (3-4 months old) by withdrawing blood from the femoral artery to a mean arterial pressure of 50 mmHg. Animals were kept in shock for 3 h, at which time they were rapidly resuscitated by returning their shed blood. At the time of resuscitation and every hour thereafter, one group of animals received C-peptide (280 nmol/kg), whereas another group received vehicle. Hemorrhagic shock resulted in significant rise in plasma levels of creatinine and elevated kidney neutrophil infiltration as evaluated by myeloperoxidase activity in vehicle-treated rats in comparison with sham rats, thus suggesting kidney injury. Treatment with C-peptide significantly attenuated the rise in creatinine and kidney myeloperoxidase activity when compared with vehicle group. At a molecular level, these effects of C-peptide were associated with reduced expression of the c-Fos subunit and reduced activation of the proinflammatory kinases, extracellular signal-regulated kinase 1/2 (ERK 1/2), and c-Jun N-terminal kinase and subsequently reduced DNA binding of activator protein 1 in the kidney. Thus, our data suggest that C-peptide may exert renoprotective effects after hemorrhagic shock by modulating activator protein 1 signaling.

  10. Pelvic Inflammatory Disease (PID)

    MedlinePlus

    Pelvic Inflammatory Disease (PID) - CDC Fact Sheet Untreated sexually transmitted diseases (STDs) can cause pelvic inflammatory disease (PID), a ... tubal blockage; •• Ectopic pregnancy (pregnancy outside the womb); •• Infertility (inability to get pregnant); •• Long-term pelvic/abdominal ...

  11. Pelvic Inflammatory Disease

    MedlinePlus

    ... Weström, L., Joesoef, R., Reynolds, G., Hagdu, A., Thompson, S.E. (1992). Pelvic inflammatory disease and fertility. A ... Weström, L., Joesoef, R., Reynolds, G., Hagdu, A., Thompson, S.E. (1992). Pelvic inflammatory disease and fertility. A ...

  12. Curcumin in inflammatory diseases.

    PubMed

    Shehzad, Adeeb; Rehman, Gauhar; Lee, Young Sup

    2013-01-01

    Curcumin (diferuloylmethane), a yellow coloring agent extracted from turmeric is also used as a remedy for the treatment and prevention of inflammatory diseases. Acute and chronic inflammation is a major factor in the progression of obesity, type II diabetes, arthritis, pancreatitis, cardiovascular, neurodegenerative and metabolic diseases, as well as certain types of cancer. Turmeric has a long history of use in Ayurvedic medicine for the treatment of inflammatory disorders. Recent studies on the efficacy and therapeutic applicability of turmeric have suggested that the active ingredient of tumeric is curcumin. Further, compelling evidence has shown that curcumin has the ability to inhibit inflammatory cell proliferation, invasion, and angiogenesis through multiple molecular targets and mechanisms of action. Curcumin is safe, non-toxic, and mediates its anti-inflammatory effects through the down-regulation of inflammatory transcription factors, cytokines, redox status, protein kinases, and enzymes that all promote inflammation. In addition, curcumin induces apoptosis through mitochondrial and receptor-mediated pathways, as well as activation of caspase cascades. In the current study, the anti-inflammatory effects of curcumin were evaluated relative to various chronic inflammatory diseases. Based on the available pharmacological data obtained from in vitro and in vivo research, as well as clinical trials, an opportunity exists to translate curcumin into clinics for the prevention of inflammatory diseases in the near future.

  13. [Inflammatory neuropathies and multineuritis].

    PubMed

    Kuntzer, Thierry; Chofflon, Michel

    2009-12-02

    Inflammatory neuropathies include those neuropathies in which the diagnosis, outcome and type of treatment are badly known, the reason of this review. They are expressed as diffuse (such as CIDP and ganglionopathies), multifocal (vasculitic neuropathy) or focal (MMN; plexopathies; immune reconstitution inflammatory syndrome). These forms of neuropathies are important to be known because the beneficial therapeutic possibilities of immunosuppression.

  14. Cyclic Opioid Peptides.

    PubMed

    Remesic, Michael; Lee, Yeon Sun; Hruby, Victor J

    2016-01-01

    For decades the opioid receptors have been an attractive therapeutic target for the treatment of pain. Since the first discovery of enkephalin, approximately a dozen endogenous opioid peptides have been known to produce opioid activity and analgesia, but their therapeutics have been limited mainly due to low blood brain barrier penetration and poor resistance to proteolytic degradation. One versatile approach to overcome these drawbacks is the cyclization of linear peptides to cyclic peptides with constrained topographical structure. Compared to their linear parents, cyclic analogs exhibit better metabolic stability, lower offtarget toxicity, and improved bioavailability. Extensive structure-activity relationship studies have uncovered promising compounds for the treatment of pain as well as further elucidate structural elements required for selective opioid receptor activity. The benefits that come with employing cyclization can be further enhanced through the generation of polycyclic derivatives. Opioid ligands generally have a short peptide chain and thus the realm of polycyclic peptides has yet to be explored. In this review, a brief history of designing ligands for the opioid receptors, including classic linear and cyclic ligands, is discussed along with recent approaches and successes of cyclic peptide ligands for the receptors. Various scaffolds and approaches to improve bioavailability are elaborated and concluded with a discourse towards polycyclic peptides.

  15. Inhibiting inflammatory cytokines.

    PubMed

    Kluth, D C; Rees, A J

    1996-11-01

    Acute glomerulonephritis is a common cause of renal dysfunction and ultimately renal failure. The inflammation involved is a tightly regulated response with pro- and anti-inflammatory cytokines playing key roles. Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are the principal pro-inflammatory cytokines produced by intrinsic cells and infiltrating leukocytes. IL-1 and TNF can be directly antagonized using IL-1 receptor antagonist (IL-1ra) or binding proteins such as soluble receptors or antibodies. Alternatively, cytokines with anti-inflammatory properties can be used to decrease IL-1 and TNF synthesis, increase the production of their natural antagonists and deactivate inflammatory cells such as macrophages. This review will focus on these anti-inflammatory cytokines, principally IL-4, IL-6, IL-10 and IL-13, and highlight recent research of their activities in existing models of renal disease. The results of these experiments offer a promising new avenue of treatment.

  16. Pediatric inflammatory bowel disease

    PubMed Central

    Diefenbach, Karen A; Breuer, Christopher K

    2006-01-01

    Inflammatory bowel disease is an important cause of gastrointestinal pathology in children and adolescents. The incidence of pediatric inflammatory bowel disease is increasing; therefore, it is important for the clinician to be aware of the presentation of this disease in the pediatric population. Laboratory tests, radiology studies, and endoscopic procedures are helpful in diagnosing inflammatory bowel disease and differentiating between Crohn’s disease and ulcerative colitis. Once diagnosed, the goal of medical management is to induce remission of disease while minimizing the side effects of the medication. Specific attention needs to be paid to achieving normal growth in this susceptible population. Surgical management is usually indicated for failure of medical management, complication, or malignancy. Algorithms for diagnostic evaluation and treatment of pediatric inflammatory bowel disease are presented. The specific psychosocial issues facing these patients are also discussed in this review as are the future goals of research in the complex problem of pediatric inflammatory bowel disease. PMID:16718840

  17. Epithelial restitution and wound healing in inflammatory bowel disease

    PubMed Central

    Sturm, Andreas; Dignass, Axel U

    2008-01-01

    Inflammatory bowel disease is characterized by a chronic inflammation of the intestinal mucosa. The mucosal epithelium of the alimentary tract constitutes a key element of the mucosal barrier to a broad spectrum of deleterious substances present within the intestinal lumen including bacterial microorganisms, various dietary factors, gastrointestinal secretory products and drugs. In addition, this mucosal barrier can be disturbed in the course of various intestinal disorders including inflammatory bowel diseases. Fortunately, the integrity of the gastrointestinal surface epithelium is rapidly reestablished even after extensive destruction. Rapid resealing of the epithelial barrier following injuries is accomplished by a process termed epithelial restitution, followed by more delayed mechanisms of epithelial wound healing including increased epithelial cell proliferation and epithelial cell differentiation. Restitution of the intestinal surface epithelium is modulated by a range of highly divergent factors among them a broad spectrum of structurally distinct regulatory peptides, variously described as growth factors or cytokines. Several regulatory peptide factors act from the basolateral site of the epithelial surface and enhance epithelial cell restitution through TGF-β-dependent pathways. In contrast, members of the trefoil factor family (TFF peptides) appear to stimulate epithelial restitution in conjunction with mucin glycoproteins through a TGF-β-independent mechanism from the apical site of the intestinal epithelium. In addition, a number of other peptide molecules like extracellular matrix factors and blood clotting factors and also non-peptide molecules including phospholipids, short-chain fatty acids (SCFA), adenine nucleotides, trace elements and pharmacological agents modulate intestinal epithelial repair mechanisms. Repeated damage and injury of the intestinal surface are key features of various intestinal disorders including inflammatory bowel

  18. Peptides conjugated to gold nanoparticles induce macrophage activation.

    PubMed

    Bastús, Neus G; Sánchez-Tilló, Ester; Pujals, Silvia; Farrera, Consol; Kogan, Marcelo J; Giralt, Ernest; Celada, Antonio; Lloberas, Jorge; Puntes, Victor

    2009-02-01

    Macrophages that react against pathogenic organisms can also be activated with artificial nanometric units consisting of gold nanoparticles (Au NPs) with a peptide coating. Using bone marrow-derived macrophages, here we show that these cells have the capacity to recognize Au NPs once conjugated to two biomedically relevant peptides, the amyloid growth inhibitory peptide (AGIP) and the sweet arrow peptide (SAP), while they do not recognize peptides or NPs alone. The recognition of these conjugates by macrophages is mediated by a pattern recognition receptor, the TLR-4. Consequently, pro-inflammatory cytokines such as TNF-alpha, IL-1 beta and IL-6, as well as nitric oxide synthase were induced and macrophage proliferation was stopped when exposed to the peptide-conjugated Au NPs. Contamination by lipopolysaccharide in our experimental system was excluded. Furthermore, macrophage activation appeared to be independent of peptide length and polarity. As a result of macrophage activation, conjugated Au NPs were internalized and processed. These results open up a new avenue in the world of adjuvants and illustrate the basic requirements for the design of NP conjugates that efficiently reach their target.

  19. Targeted Peptide Specificity

    DTIC Science & Technology

    1989-01-31

    the conformation of small natural peptide ligands. In the last year two peptides were investigaýed by 2D-NMR,(j2.- conotoxin SI, which targets to the...targets. Although these venoms are very complex, we have focused on three groups of peptide toxins, the a, j and w- conotoxins which target to nicotinic...grant period are summarized below.) In addition, the 2D-NMR work is continuing and in addition to examining one of the conotoxins specific for the

  20. An Immunosuppressant Peptide from the Hard Tick Amblyomma variegatum

    PubMed Central

    Tian, Yufeng; Chen, Wenlin; Mo, Guoxiang; Chen, Ran; Fang, Mingqian; Yedid, Gabriel; Yan, Xiuwen

    2016-01-01

    Ixodid ticks are well known for spreading transmitted tick-borne pathogens while being attached to their hosts for almost 1–2 weeks to obtain blood meals. Thus, they must secrete many immunosuppressant factors to combat the hosts’ immune system. In the present work, we investigated an immunosuppressant peptide of the hard tick Amblyomma variegatum. This peptide, named amregulin, is composed of 40 residues with an amino acid sequence of HLHMHGNGATQVFKPRLVLKCPNAAQLIQPGKLQRQLLLQ. A cDNA of the precursor peptide was obtained from the National Center for Biotechnology Information (NCBI, Bethesda, MD, USA). In rat splenocytes, amregulin exerts significant anti-inflammatory effects by inhibiting the secretion of inflammatory factors in vitro, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-8 (IL-8) and interferon-gamma (IFN-γ). In rat splenocytes, treated with amregulin, compared to lipopolysaccharide (LPS) alone, the inhibition of the above inflammatory factors was significant at all tested concentrations (2, 4 and 8 µg/mL). Amregulin shows strong free radical scavenging and antioxidant activities (5, 10 and 20 µg/mL) in vitro. Amregulin also significantly inhibits adjuvant-induced paw inflammation in mouse models in vivo. This peptide may facilitate the ticks’ successful blood feeding and may lead to host immunotolerance of the tick. These findings have important implications for the understanding of tick-host interactions and the co-evolution between ticks and the viruses that they bear. PMID:27153086

  1. Inflammation in Diabetic Encephalopathy is Prevented by C-Peptide

    PubMed Central

    Sima, Anders A.F.; Zhang, Weixian; Kreipke, Christian W.; Rafols, José A.; Hoffman, William H.

    2009-01-01

    Encephalopathy is an increasingly recognized complication of type 1 diabetes. The underlying mechanisms are not well understood, although insulin deficiency has been implicated. The spontaneously diabetic BB/Wor-rat develops neuro-behavioral deficits and neuronal cell death in hippocampus and frontal cortex, which can be prevented by insulinomimetic C-peptide. Here we examined whether contributing factors such as activation of innate immune mediators are responsive to C-peptide replacement. Seven-month diabetic BB/Wor-rats and those treated with full C-peptide replacement were compared to age-matched control rats. Hippocampi of diabetic rats showed upregulation of RAGE and NF-κB, the former being localized to proliferating astrocytes. These changes were associated with increased expression of TNF-α, IL-1β, IL-2 and IL-6 in hippocampi of diabetic rats. Full C-peptide replacement, which did not induce hyperglycemia, resulted in significant prevention of upregulation of RAGE expression, activation of NF-κB and activation of pro-inflammatory factors. In conclusion, impaired insulin activity is associated with upregulation of RAGE and pro-inflammatory factors, and these are likely to contribute to previously described oxidative and apoptotic neuronal cell death. Replacement of insulinomimetic C-peptide significantly prevents this cascade of events. PMID:19557294

  2. Inflammation in Diabetic Encephalopathy is Prevented by C-Peptide.

    PubMed

    Sima, Anders A F; Zhang, Weixian; Kreipke, Christian W; Rafols, José A; Hoffman, William H

    2009-01-01

    Encephalopathy is an increasingly recognized complication of type 1 diabetes. The underlying mechanisms are not well understood, although insulin deficiency has been implicated. The spontaneously diabetic BB/Wor-rat develops neuro-behavioral deficits and neuronal cell death in hippocampus and frontal cortex, which can be prevented by insulinomimetic C-peptide. Here we examined whether contributing factors such as activation of innate immune mediators are responsive to C-peptide replacement. Seven-month diabetic BB/Wor-rats and those treated with full C-peptide replacement were compared to age-matched control rats. Hippocampi of diabetic rats showed upregulation of RAGE and NF-kappaB, the former being localized to proliferating astrocytes. These changes were associated with increased expression of TNF-alpha, IL-1beta, IL-2 and IL-6 in hippocampi of diabetic rats. Full C-peptide replacement, which did not induce hyperglycemia, resulted in significant prevention of upregulation of RAGE expression, activation of NF-kappaB and activation of pro-inflammatory factors. In conclusion, impaired insulin activity is associated with upregulation of RAGE and pro-inflammatory factors, and these are likely to contribute to previously described oxidative and apoptotic neuronal cell death. Replacement of insulinomimetic C-peptide significantly prevents this cascade of events.

  3. Anti-antimicrobial Peptides

    PubMed Central

    Ryan, Lloyd; Lamarre, Baptiste; Diu, Ting; Ravi, Jascindra; Judge, Peter J.; Temple, Adam; Carr, Matthew; Cerasoli, Eleonora; Su, Bo; Jenkinson, Howard F.; Martyna, Glenn; Crain, Jason; Watts, Anthony; Ryadnov, Maxim G.

    2013-01-01

    Antimicrobial or host defense peptides are innate immune regulators found in all multicellular organisms. Many of them fold into membrane-bound α-helices and function by causing cell wall disruption in microorganisms. Herein we probe the possibility and functional implications of antimicrobial antagonism mediated by complementary coiled-coil interactions between antimicrobial peptides and de novo designed antagonists: anti-antimicrobial peptides. Using sequences from native helical families such as cathelicidins, cecropins, and magainins we demonstrate that designed antagonists can co-fold with antimicrobial peptides into functionally inert helical oligomers. The properties and function of the resulting assemblies were studied in solution, membrane environments, and in bacterial culture by a combination of chiroptical and solid-state NMR spectroscopies, microscopy, bioassays, and molecular dynamics simulations. The findings offer a molecular rationale for anti-antimicrobial responses with potential implications for antimicrobial resistance. PMID:23737519

  4. Insulin C-peptide

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/003701.htm Insulin C-peptide test To use the sharing features ... a product that is created when the hormone insulin is produced and released into the body. The ...

  5. [Auto-inflammatory syndromes].

    PubMed

    Grateau, Gilles

    2005-02-28

    Auto-inflammatory syndromes are a group of hereditary diseases characterised by intermittent bouts of clinical inflammation with focal organ involvement mainly: abdomen, musculoskeletal system and skin. The most frequent is familial Mediterranean fever, which affects patients of Mediterranean descent all over the world. Three other types have been recently clinically as well as genetically characterised. A thorough diagnosis is warranted, as clinical and therapeutic management is specific for each of these diseases, as underlied by a specific inflammatory pathway. This new group of diseases has already opened new avenues in our understanding of the inflammatory response.

  6. Peptide Optical waveguides.

    PubMed

    Handelman, Amir; Apter, Boris; Shostak, Tamar; Rosenman, Gil

    2017-02-01

    Small-scale optical devices, designed and fabricated onto one dielectric substrate, create integrated optical chip like their microelectronic analogues. These photonic circuits, based on diverse physical phenomena such as light-matter interaction, propagation of electromagnetic waves in a thin dielectric material, nonlinear and electro-optical effects, allow transmission, distribution, modulation, and processing of optical signals in optical communication systems, chemical and biological sensors, and more. The key component of these optical circuits providing both optical processing and photonic interconnections is light waveguides. Optical confinement and transmitting of the optical waves inside the waveguide material are possible due to the higher refractive index of the waveguides in comparison with their surroundings. In this work, we propose a novel field of bionanophotonics based on a new concept of optical waveguiding in synthetic elongated peptide nanostructures composed of ordered peptide dipole biomolecules. New technology of controllable deposition of peptide optical waveguiding structures by nanofountain pen technique is developed. Experimental studies of refractive index, optical transparency, and linear and nonlinear waveguiding in out-of-plane and in-plane diphenylalanine peptide nanotubes have been conducted. Optical waveguiding phenomena in peptide structures are simulated by the finite difference time domain method. The advantages of this new class of bio-optical waveguides are high refractive index contrast, wide spectral range of optical transparency, large optical nonlinearity, and electro-optical effect, making them promising for new applications in integrated multifunctional photonic circuits. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

  7. Melanins from opioid peptides.

    PubMed

    Rosei, M A

    1996-12-01

    Opioid peptides and other Tyr-NH2-terminal peptides are substrates in vitro for mushroom and sepia tyrosine, giving rise to synthetic melanins retaining the peptide moiety (opiomelanins). The melanopeptides are characterized by a total solubility in hydrophylic solvents at neutral and basic pH. Opioid peptides (enkephalins, endorphins, and esorphins), if oxidized by tyrosinase in the presence of Dopa, are easily incorporated into Dopa-melanin, producing mixed-type pigments that can also be solubilized in hydrophylic solvents. Melanins derived from opioid peptides exhibit paramagnetism, as evidenced by an EPR spectrum identical to that of Dopa-melanin. However, the presence of the linked peptide chain is able to influence dramatically the electron transfer properties and the oxidizing behaviour of the melanopeptides, so that whereas Tyr-Gly-melanin appears to behave as Dopa-melanin, Enk-melanin does not exhibit any oxidizing activity. Opiomelanins are characterized by a peculiar UV-VIS spectrum; that is, by the presence of a distinct peak (330 nm) that disappears upon chemical treatment by acid hydrolysis. Opiomelanins are stable pigments at neutral and basic pH in the dark, whereas the addition of H2O2 leads to a 15% degradation. Under stimulated solar illumination, opiomelanins are more easily destroyed with respect to Dopa-melanin, with increasing degradation when exposed to increased hydrogen peroxide concentrations and more alkaline pH. Some speculations on the possible existence and role of opiomelanins have been outlined.

  8. An anti-infective synthetic peptide with dual antimicrobial and immunomodulatory activities

    PubMed Central

    Silva, O. N.; de la Fuente-Núñez, C.; Haney, E. F.; Fensterseifer, I. C. M.; Ribeiro, S. M.; Porto, W. F.; Brown, P.; Faria-Junior, C.; Rezende, T. M. B.; Moreno, S. E.; Lu, T. K.; Hancock, R. E. W.; Franco, O. L.

    2016-01-01

    Antibiotic-resistant infections are predicted to kill 10 million people per year by 2050, costing the global economy $100 trillion. Therefore, there is an urgent need to develop alternative technologies. We have engineered a synthetic peptide called clavanin-MO, derived from a marine tunicate antimicrobial peptide, which exhibits potent antimicrobial and immunomodulatory properties both in vitro and in vivo. The peptide effectively killed a panel of representative bacterial strains, including multidrug-resistant hospital isolates. Antimicrobial activity of the peptide was demonstrated in animal models, reducing bacterial counts by six orders of magnitude, and contributing to infection clearance. In addition, clavanin-MO was capable of modulating innate immunity by stimulating leukocyte recruitment to the site of infection, and production of immune mediators GM-CSF, IFN-γ and MCP-1, while suppressing an excessive and potentially harmful inflammatory response by increasing synthesis of anti-inflammatory cytokines such as IL-10 and repressing the levels of pro-inflammatory cytokines IL-12 and TNF-α. Finally, treatment with the peptide protected mice against otherwise lethal infections caused by both Gram-negative and -positive drug-resistant strains. The peptide presented here directly kills bacteria and further helps resolve infections through its immune modulatory properties. Peptide anti-infective therapeutics with combined antimicrobial and immunomodulatory properties represent a new approach to treat antibiotic-resistant infections. PMID:27804992

  9. Molecular Grafting onto a Stable Framework Yields Novel Cyclic Peptides for the Treatment of Multiple Sclerosis

    PubMed Central

    2013-01-01

    Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) and is characterized by the destruction of myelin and axons leading to progressive disability. Peptide epitopes from CNS proteins, such as myelin oligodendrocyte glycoprotein (MOG), possess promising immunoregulatory potential for treating MS; however, their instability and poor bioavailability is a major impediment for their use clinically. To overcome this problem, we used molecular grafting to incorporate peptide sequences from the MOG35–55 epitope onto a cyclotide, which is a macrocyclic peptide scaffold that has been shown to be intrinsically stable. Using this approach, we designed novel cyclic peptides that retained the structure and stability of the parent scaffold. One of the grafted peptides, MOG3, displayed potent ability to prevent disease development in a mouse model of MS. These results demonstrate the potential of bioengineered cyclic peptides for the treatment of MS. PMID:24147816

  10. Inflammatory bowel disease - slideshow

    MedlinePlus

    ... presentations/100171.htm Inflammatory bowel disease - series—Normal anatomy To ... gastrointestinal tract starts at the mouth, which leads to the esophagus, stomach, small intestine, colon, and finally, the rectum and ...

  11. Pelvic Inflammatory Disease

    MedlinePlus

    Pelvic inflammatory disease (PID) is an infection and inflammation of the uterus, ovaries, and other female reproductive organs. It causes scarring ... United States. Gonorrhea and chlamydia, two sexually transmitted diseases, are the most common causes of PID. Other ...

  12. Inflammatory biomarkers for AMD.

    PubMed

    Stanton, Chloe M; Wright, Alan F

    2014-01-01

    Age-related macular degeneration (AMD) is the leading cause of blindness worldwide, affecting an estimated 50 million individuals aged over 65 years.Environmental and genetic risk-factors implicate chronic inflammation in the etiology of AMD, contributing to the formation of drusen, retinal pigment epithelial cell dysfunction and photoreceptor cell death. Consistent with a role for chronic inflammation in AMD pathogenesis, several inflammatory mediators, including complement components, chemokines and cytokines, are elevated at both the local and systemic levels in AMD patients. These mediators have diverse roles in the alternative complement pathway, including recruitment of inflammatory cells, activation of the inflammasome, promotion of neovascularisation and in the resolution of inflammation. The utility of inflammatory biomarkers in assessing individual risk and progression of the disease is controversial. However, understanding the role of these inflammatory mediators in AMD onset, progression and response to treatment may increase our knowledge of disease pathogenesis and provide novel therapeutic options in the future.

  13. Pelvic Inflammatory Disease

    MedlinePlus

    ... Human Papillomavirus (HPV) Pelvic Inflammatory Disease (PID) STDs & Infertility STDs & Pregnancy Syphilis Trichomoniasis Other STDs See Also ... the upper genital tract. PID can lead to infertility and permanent damage of a woman’s reproductive organs. ...

  14. Inflammatory Breast Cancer

    MedlinePlus

    ... red, or inflamed. Inflammatory breast cancer is rare, accounting for 1 to 5 percent of all breast ... Publications Site Map Digital Standards for NCI Websites POLICIES Accessibility Comment Policy Disclaimer FOIA Privacy & Security Reuse & ...

  15. Non-peptide ligand binding to the formyl peptide receptor FPR2--A comparison to peptide ligand binding modes.

    PubMed

    Stepniewski, Tomasz M; Filipek, Slawomir

    2015-07-15

    Ligands of the FPR2 receptor initiate many signaling pathways including activation of phospholipase C, protein kinase C, the mitogen-activated protein kinase, and phosphatidylinositol 3-kinase/protein kinase B pathway. The possible actions include also calcium flux, superoxide generation, as well as migration and proliferation of monocytes. FPR2 activation may induce a pro- and anti-inflammatory effect depending on the ligand type. It is also found that this receptor is involved in tumor growth. Most of currently known FPR2 ligands are agonists since they were designed based on N-formyl peptides, which are natural agonists of formyl receptors. Since the non-peptide drugs are indispensable for effective treatment strategies, we performed a docking study of such ligands employing a generated dual template homology model of the FPR2 receptor. The study revealed different binding modes of particular classes of these drugs. Based on the obtained docking poses we proposed a detailed location of three hydrophobic pockets in orthosteric binding site of FPR2. Our model emphasizes the importance of aromatic stacking, especially with regard to residues His102(3.29) and Phe257(6.51), for binding of FPR2 ligands. We also identified other residues important for non-peptide ligand binding in the binding site of FPR2. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Anti-inflammatory Diets.

    PubMed

    Sears, Barry

    2015-01-01

    Chronic disease is driven by inflammation. This article will provide an overview on how the balance of macronutrients and omega-6 and omega-3 fatty acids in the diet can alter the expression of inflammatory genes. In particular, how the balance of the protein to glycemic load of a meal can alter the generation of insulin and glucagon and the how the balance of omega-6 and omega-3 fatty acids can effect eicosanoid formation. Clinical results on the reduction of inflammation following anti-inflammatory diets are discussed as well as the molecular targets of anti-inflammatory nutrition. To overcome silent inflammation requires an anti-inflammatory diet (with omega-3s and polyphenols, in particular those of Maqui). The most important aspect of such an anti-inflammatory diet is the stabilization of insulin and reduced intake of omega-6 fatty acids. The ultimate treatment lies in reestablishing hormonal and genetic balance to generate satiety instead of constant hunger. Anti-inflammatory nutrition, balanced 40:30:30 with caloric restriction, should be considered as a form of gene silencing technology, in particular the silencing of the genes involved in the generation of silent inflammation. To this anti-inflammatory diet foundation supplemental omega-3 fatty acids at the level of 2-3 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day should be added. Finally, a diet rich in colorful, nonstarchy vegetables would contribute adequate amounts of polyphenols to help not only to inhibit nuclear factor (NF)-κB (primary molecular target of inflammation) but also activate AMP kinase. Understanding the impact of an anti-inflammatory diet on silent inflammation can elevate the diet from simply a source of calories to being on the cutting edge of gene-silencing technology.

  17. [Inflammaging. Aging inflammatory origin].

    PubMed

    Navarrete-Reyes, Ana Patricia; Montaña-Alvarez, Mariano

    2009-01-01

    The association between the increase in life expectancy in humans and age-related changes in the immune system promotes that individuals are exposed longer to endogenous and environment antigens which allows an activation of the innate immune system and the subsequent establishment of a low grade chronic inflammation state with an increased expression of proinflammatory cytokines (tumor necrosis factor alpha, interleukin 6, etc.). This inflammatory state referred as inflammaging is characterized by a inflammatory origin of aging given by the activation of cellular systems responsible of gene promotion and suppression as the nuclear factor kappa B, sirtuins, forkhead box O and KLOTHO, who are directly or indirectly involved in cellular mechanisms of resistance to oxidative stress, apoptosis and nucleic acids transcriptional mistakes repair. The activation of these cellular systems is associated with the pathogenesis of several chronic and degenerative diseases such as Alzheimer's disease, late-onset diabetes or cardiovascular diseases. However, we are placed in a crossroad because we can not establish whether this inflammatory state observed in the aging process is responsible of development of degenerative diseases or if the presences of these chronic diseases are responsible for this inflammatory state of aging. Evidence in centenarians who are healthy and have preserved functional status has shown that there is a chronic inflammatory state present among them but is balanced by a higher expression of anti-inflammatory molecules.

  18. Anti-inflammatory role of obestatin in autoimmune myocarditis.

    PubMed

    Pamukcu, Ozge; Baykan, Ali; Bayram, Latife Cakir; Narin, Figen; Cetin, Nazmi; Narin, Nazmi; Argun, Mustafa; Ozyurt, Abdullah; Uzum, Kazim

    2016-01-01

    Obestatin is a popular endogeneous peptide, known to have an autoimmune regulatory effect on energy metabolism and the gastrointestinal system. Studies regarding the anti-inflammatory effects of obestatin are scarce. The aim of this study was to show the anti-inflammatory effect of obestatin in an experimental model of autoimmune myocarditis in rats. Experimental autoimmune myocarditis was induced in Lewis rats by immunization with subcutaneous administration of porcine cardiac myosin, twice at 7-day intervals. Intraperitoneal pretreatment with obestatin (50 μg/kg) was started before the induction of myocarditis and continued for 3 weeks. The severity of myocarditis was evidenced by clinical, echocardiographic and histological findings. In addition, by-products of neutrophil activation, lipid peroxidation, inflammatory and anti-inflammatory cytokines were measured in serum. Obestatin significantly ameliorated the clinical and histopathological severity of autoimmune myocarditis. Therapeutic effects of obestatin in myocarditis were associated with reduced lipid peroxidation, suppression of polymorphonuclear leukocyte infiltration and enhancement of glutathione synthesis, inhibition of serum inflammatory and activation of anti-inflammatory cytokines. Histopathologically, the left ventricle was significantly dilated, and its wall thickened, along with widespread lymphocytic and histocytic infiltration. The myocardium was severely infiltrated with relatively large mononuclear cells. These histopathological changes were observed in lesser degrees in obestatin-treated rats. This study demonstrated a novel anti-inflammatory effect of obestatin in an experimental model of autoimmune myocarditis. Consequently, obestatin administration may represent a promising therapeutic approach for myocarditis and dilated cardiomyopathy in the future.

  19. Inflammatory Cyclooxygenase Activity and PGE2 Signaling in Models of Alzheimer’s Disease

    PubMed Central

    Johansson, Jenny U.; Woodling, Nathaniel S.; Shi, Ju; Andreasson, Katrin I.

    2015-01-01

    The inflammatory response is a fundamental driving force in the pathogenesis of Alzheimer’s disease (AD). In the setting of accumulating immunogenic Aß peptide assemblies, microglia, the innate immune cells of the brain, generate a non-resolving immune response and fail to adequately clear accumulating Aß peptides, accelerating neuronal and synaptic injury. Pathological, biomarker, and imaging studies point to a prominent role of the innate immune response in AD development, and the molecular components of this response are beginning to be unraveled. The inflammatory cyclooxygenase-PGE2 pathway is implicated in pre-clinical development of AD, both in epidemiology of normal aging populations and in transgenic mouse models of Familial AD. The cyclooxygenase-PGE2 pathway modulates the inflammatory response to accumulating Aß peptides through actions of specific E-prostanoid G-protein coupled receptors.

  20. Linear Peptides in Intracellular Applications.

    PubMed

    Zuconelli, Cristiane R; Brock, Roland; Adjobo-Hermans, Merel J W

    2017-01-01

    To this point, efforts to develop therapeutic peptides for intracellular applications were guided by the perception that unmodified linear peptides are highly unstable and therefore structural modifications are required to reduce proteolytic breakdown. Largely, this concept is a consequence of the fact that most research on intracellular peptides hitherto has focused on peptide degradation in the context of antigen processing, rather than on peptide stability. Interestingly, inside cells, endogenous peptides lacking any chemical modifications to enhance stability escape degradation to the point that they may even modulate intracellular signaling pathways. In addition, many unmodified synthetic peptides designed to interfere with intracellular signaling, following introduction into cells, have the expected activity demonstrating that biologically relevant concentrations can be reached. This review provides an overview of results and techniques relating to the exploration and application of linear, unmodified peptides. After an introduction to intracellular peptide turnover, the review mentions examples for synthetic peptides as modulators of intracellular signaling, introduces endogenous peptides with bioactivity, techniques to measure peptide stability, and peptide delivery. Future experiments should elucidate the rules needed to predict promising peptide candidates. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Immunomodulatory effects of anti-microbial peptides.

    PubMed

    Otvos, Laszlo

    2016-09-01

    Anti-microbial peptides (AMPs) were originally thought to exert protecting actions against bacterial infection by disintegrating bacterial membranes. Upon identification of internal bacterial targets, the view changed and moved toward inhibition of prokaryote-specific biochemical processes. However, the level of none of these activities can explain the robust efficacy of some of these peptides in animal models of systemic and cutaneous infections. A rapidly growing panel of reports suggests that AMPs, now called host-defense peptides (HDPs), act through activating the immune system of the host. This includes recruitment and activation of macrophages and mast cells, inducing chemokine production and altering NF-κB signaling processes. As a result, both pro- and anti-inflammatory responses are elevated together with activation of innate and adaptive immunity mechanisms, wound healing, and apoptosis. HDPs sterilize the systemic circulation and local injury sites significantly more efficiently than pure single-endpoint in vitro microbiological or biochemical data would suggest and actively aid recovering from tissue damage after or even without bacterial infections. However, the multiple and, often opposing, immunomodulatory functions of HDPs require exceptional care in therapeutic considerations.

  2. Electron transfer in peptides.

    PubMed

    Shah, Afzal; Adhikari, Bimalendu; Martic, Sanela; Munir, Azeema; Shahzad, Suniya; Ahmad, Khurshid; Kraatz, Heinz-Bernhard

    2015-02-21

    In this review, we discuss the factors that influence electron transfer in peptides. We summarize experimental results from solution and surface studies and highlight the ongoing debate on the mechanistic aspects of this fundamental reaction. Here, we provide a balanced approach that remains unbiased and does not favor one mechanistic view over another. Support for a putative hopping mechanism in which an electron transfers in a stepwise manner is contrasted with experimental results that support electron tunneling or even some form of ballistic transfer or a pathway transfer for an electron between donor and acceptor sites. In some cases, experimental evidence suggests that a change in the electron transfer mechanism occurs as a result of donor-acceptor separation. However, this common understanding of the switch between tunneling and hopping as a function of chain length is not sufficient for explaining electron transfer in peptides. Apart from chain length, several other factors such as the extent of the secondary structure, backbone conformation, dipole orientation, the presence of special amino acids, hydrogen bonding, and the dynamic properties of a peptide also influence the rate and mode of electron transfer in peptides. Electron transfer plays a key role in physical, chemical and biological systems, so its control is a fundamental task in bioelectrochemical systems, the design of peptide based sensors and molecular junctions. Therefore, this topic is at the heart of a number of biological and technological processes and thus remains of vital interest.

  3. Cyclization in opioid peptides.

    PubMed

    Piekielna, Justyna; Perlikowska, Renata; Gach, Katarzyna; Janecka, Anna

    2013-06-01

    Endogenous opioid peptides have been studied extensively as potential therapeutics for the treatment of pain. The major problems of using natural opioid peptides as drug candidates are their poor receptor specificity, metabolic instability and inability to reach the brain after systemic administration. A lot of synthetic efforts have been made to opioid analogs with improved pharmacological properties. One important structural modification leading to such analogs is cyclization of linear sequences. Intramolecular cyclization has been shown to improve biological properties of various bioactive peptides. Cyclization reduces conformational freedom responsible for the simultaneous activation of two or more receptors, increases metabolic stability and lipophilicity which may result in a longer half-life and easier penetration across biological membranes. This review deals with various strategies that have been employed to synthesize cyclic analogs of opioid peptides. Discussed are such bridging bonds as amide and amine linkages, sulfur-containing bonds, including monosulfide, disulfide and dithioether bridges, bismethylene bonds, monosulfide bridges of lanthionine and, finally, carbonyl and guanidine linkages. Opioid affinities and activities of cyclic analogs are given and compared with linear opioid peptides. Analgesic activities of analogs evaluated in the in vivo pain tests are also discussed.

  4. Antimicrobial Peptides from Plants

    PubMed Central

    Tam, James P.; Wang, Shujing; Wong, Ka H.; Tan, Wei Liang

    2015-01-01

    Plant antimicrobial peptides (AMPs) have evolved differently from AMPs from other life forms. They are generally rich in cysteine residues which form multiple disulfides. In turn, the disulfides cross-braced plant AMPs as cystine-rich peptides to confer them with extraordinary high chemical, thermal and proteolytic stability. The cystine-rich or commonly known as cysteine-rich peptides (CRPs) of plant AMPs are classified into families based on their sequence similarity, cysteine motifs that determine their distinctive disulfide bond patterns and tertiary structure fold. Cystine-rich plant AMP families include thionins, defensins, hevein-like peptides, knottin-type peptides (linear and cyclic), lipid transfer proteins, α-hairpinin and snakins family. In addition, there are AMPs which are rich in other amino acids. The ability of plant AMPs to organize into specific families with conserved structural folds that enable sequence variation of non-Cys residues encased in the same scaffold within a particular family to play multiple functions. Furthermore, the ability of plant AMPs to tolerate hypervariable sequences using a conserved scaffold provides diversity to recognize different targets by varying the sequence of the non-cysteine residues. These properties bode well for developing plant AMPs as potential therapeutics and for protection of crops through transgenic methods. This review provides an overview of the major families of plant AMPs, including their structures, functions, and putative mechanisms. PMID:26580629

  5. Peptides in oral diseases.

    PubMed

    Lucchese, Alberta; Guida, Agostino; Petruzzi, Massimo; Capone, Giovanni; Laino, Luigi; Serpico, Rosario

    2012-01-01

    The oral cavity is home to numerous viruses and micro-organisms recognized as having a role in various oral diseases as well as in infections in other parts of the body. Indeed, in general a microbial infection underlies or is believed to underlie the ample spectrum of oral diseases, from tooth enamel decay to periodontal lesions, from candidiasis to virus-induced oral squamous cell carcinomas, and bullous autoimmune oral disorders. This clinico-pathological context stresses the need of targeted therapies to specifically kill infectious agents in a complex environment such as the oral cavity, and explains the current interest in exploring peptide-based therapeutic approaches in oral and dental research. Here, we review the therapeutic potential of antimicrobial peptides such as LL-37, beta defensins, adrenomedullin, histatins, and of various peptides modulating gene expression and immuno-biological interaction(s) in oral diseases.

  6. Molecular modeling of peptides.

    PubMed

    Kuczera, Krzysztof

    2015-01-01

    This article presents a review of the field of molecular modeling of peptides. The main focus is on atomistic modeling with molecular mechanics potentials. The description of peptide conformations and solvation through potentials is discussed. Several important computer simulation methods are briefly introduced, including molecular dynamics, accelerated sampling approaches such as replica-exchange and metadynamics, free energy simulations and kinetic network models like Milestoning. Examples of recent applications for predictions of structure, kinetics, and interactions of peptides with complex environments are described. The reliability of current simulation methods is analyzed by comparison of computational predictions obtained using different models with each other and with experimental data. A brief discussion of coarse-grained modeling and future directions is also presented.

  7. Serum peptide reactivities may distinguish neuromyelitis optica subgroups and multiple sclerosis

    PubMed Central

    Metz, Imke; Beißbarth, Tim; Ellenberger, David; Pache, Florence; Stork, Lidia; Ringelstein, Marius; Aktas, Orhan; Jarius, Sven; Wildemann, Brigitte; Dihazi, Hassan; Friede, Tim; Ruprecht, Klemens; Paul, Friedemann

    2016-01-01

    Objective: To assess in an observational study whether serum peptide antibody reactivities may distinguish aquaporin-4 (AQP4) antibody (Ab)–positive and -negative neuromyelitis optica spectrum disorders (NMOSD) and relapsing-remitting multiple sclerosis (RRMS). Methods: We screened 8,700 peptides that included human and viral antigens of potential relevance for inflammatory demyelinating diseases and random peptides with pooled sera from different patient groups and healthy controls to set up a customized microarray with 700 peptides. With this microarray, we tested sera from 66 patients with AQP4-Ab-positive (n = 16) and AQP4-Ab-negative (n = 19) NMOSD, RRMS (n = 11), and healthy controls (n = 20). Results: Differential peptide reactivities distinguished NMOSD subgroups from RRMS in 80% of patients. However, the 2 NMOSD subgroups were not well-discriminated, although those patients are clearly separated by their antibody reactivities against AQP4 in cell-based assays. Elevated reactivities to myelin and Epstein-Barr virus peptides were present in RRMS and to AQP4 and AQP1 peptides in AQP4-Ab-positive NMOSD. Conclusions: While AQP4-Ab-positive and -negative NMOSD subgroups are not well-discriminated by peptide antibody reactivities, our findings suggest that peptide antibody reactivities may have the potential to distinguish between both NMOSD subgroups and MS. Future studies should thus concentrate on evaluating peptide antibody reactivities for the differentiation of AQP4-Ab-negative NMOSD and MS. PMID:26894206

  8. Epitope peptides and immunotherapy.

    PubMed

    Tanabe, Soichi

    2007-02-01

    Allergic diseases affect atopic individuals, who synthesize specific Immunoglobulins E (IgE) to environmental allergens, usually proteins or glycoproteins. These allergens include grass and tree pollens, indoor allergens such as house dust mites and animal dander, and various foods. Because allergen-specific IgE antibodies are the main effector molecules in the immune response to allergens, many studies have focused on the identification of IgE-binding epitopes (called B cell epitopes), specific and minimum regions of allergen molecules that binds to IgE. Our initial studies have provided evidence that only four to five amino acid residues are enough to comprise an epitope, since pentapeptide QQQPP in wheat glutenin is minimally required for IgE binding. Afterwards, various kinds of B cell epitope structures have been clarified. Such information contributes greatly not only to the elucidation of the etiology of allergy, but also to the development of strategies for the treatment and prevention of allergy. Allergen-specific T cells also play an important role in allergy and are obvious targets for intervention in the disease. Currently, the principle approach is to modify B cell epitopes to prevent IgE binding while preserving T cell epitopes to retain the capacity for immunotherapy. There is mounting evidence that the administration of peptide(s) containing immunodominant T cell epitopes from an allergen can induce T cell nonresponsiveness (immunotherapy). There have been clinical studies of peptide immunotherapy performed, the most promising being for bee venom sensitivity. Clinical trials of immunotherapy for cat allergen peptide have also received attention. An alternative strategy for the generation of an effective but hypoallergenic preparation for immunotherapy is to modify T cell epitope peptides by, for example, single amino acid substitution. In this article, I will present an overview of epitopes related to allergic disease, particularly stress on

  9. Antimicrobial peptides and the skin immune defense system

    PubMed Central

    Schauber, Jürgen; Gallo, Richard L.

    2009-01-01

    Our skin is constantly challenged by microbes but is rarely infected. Cutaneous production of antimicrobial peptides (AMPs) is a primary system for protection, and expression of some AMPs further increases in response to microbial invasion. Cathelicidins are unique AMPs that protect the skin through 2 distinct pathways: (1) direct antimicrobial activity and (2) initiation of a host response resulting in cytokine release, inflammation, angiogenesis, and reepithelialization. Cathelicidin dysfunction emerges as a central factor in the pathogenesis of several cutaneous diseases, including atopic dermatitis, in which cathelicidin is suppressed; rosacea, in which cathelicidin peptides are abnormally processed to forms that induce inflammation; and psoriasis, in which cathelicidin peptide converts self-DNA to a potent stimulus in an autoinflammatory cascade. Recent work identified vitamin D3 as a major factor involved in the regulation of cathelicidin. Therapies targeting control of cathelicidin and other AMPs might provide new approaches in the management of infectious and inflammatory skin diseases. PMID:18439663

  10. Evolution of Inflammatory Diseases

    PubMed Central

    Okin, Daniel

    2013-01-01

    The association of inflammation with modern human diseases (e.g. obesity, cardiovascular disease, type 2 diabetes mellitus, cancer) remains an unsolved mystery of current biology and medicine. Inflammation is a protective response to noxious stimuli that unavoidably occurs at a cost to normal tissue function. This fundamental tradeoff between the cost and benefit of the inflammatory response has been optimized over evolutionary time for specific environmental conditions. Rapid change of the human environment due to niche construction outpaces genetic adaptation through natural selection, leading increasingly to a mismatch between the modern environment and selected traits. Consequently, multiple tradeoffs that affect human physiology are not optimized to the modern environment, leading to increased disease susceptibility. Here we examine the inflammatory response from an evolutionary perspective. We discuss unique aspects of the inflammatory response and its evolutionary history that can help explain the association between inflammation and modern human diseases. PMID:22975004

  11. Desquamative inflammatory vaginitis.

    PubMed

    Reichman, Orna; Sobel, Jack

    2014-10-01

    Desquamative inflammatory vaginitis (DIV) is an uncommon form of chronic purulent vaginitis. It occurs mainly in Caucasians with a peak occurrence in the perimenopause. Symptoms and signs are nonspecific; DIV is a diagnosis of exclusion, and other causes of purulent vaginitis should be excluded. The main symptoms include purulent discharge, vestibulo-vaginal irritation, and dyspareunia. Examination of vaginal walls shows signs of inflammation with increased erythema and petechiae. Through microscopy (wet mount) of the vaginal secretions, DIV is defined by an increase in inflammatory cells and parabasal epithelial cells (immature squamous cells). Vaginal flora is abnormal and pH is always elevated above 4.5. Although etiology and pathogenesis remain unknown, the favorable response to anti-inflammatory agents suggests that the etiology is immune mediated. Either local vaginal clindamycin or vaginal corticosteroids are adequate treatment. As a chronic condition, maintenance treatment should be considered as relapse is common. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Anti-inflammatory ingredients.

    PubMed

    Wu, Jessica

    2008-07-01

    There is a growing public awareness and concern among individuals regarding the condition of their skin, with a concomitant desire to use natural products to treat skin conditions. The increased interest in these products has spurred scientific and clinical studies evaluating the composition and clinical usefulness of natural products in the treatment of inflammatory skin dermatoses. There are numerous natural ingredients that have been demonstrated to possess anti-inflammatory properties that make formulations containing these ingredients attractive treatment options. This article summarizes the active ingredients, anti-inflammatory properties, clinical effects, and therapeutic potential of colloidal oatmeal, feverfew, licorice, aloe vera, chamomile, and turmeric. Potential therapeutic indications include erythema induced by ultraviolet light, rosacea, atopic dermatitis, sensitive and irritated skin, drug-induced skin eruptions, and psoriasis. These products may be particularly well suited as alternatives to pharmacologic therapies in chronic conditions for which long-term use is required.

  13. Inflammatory Manifestations of Lymphedema

    PubMed Central

    Ly, Catherine L.; Kataru, Raghu P.; Mehrara, Babak J.

    2017-01-01

    Lymphedema results from lymphatic insufficiency leading to a progressive inflammatory process that ultimately manifests as discomfort, recurrent infections, and, at times, secondary malignancy. Collectively, these morbidities contribute to an overall poor quality of life. Although there have been recent advances in microsurgical interventions, a conservative palliative approach remains the mainstay of treatment for this disabling disease. The absence of a cure is due to an incomplete understanding of the pathophysiological changes that result in lymphedema. A histological hallmark of lymphedema is inflammatory cell infiltration and recent studies with animal models and clinical biopsy specimens have suggested that this response plays a key role in the pathology of the disease. The purpose of this report is to provide an overview of the ongoing research in and the current understanding of the inflammatory manifestations of lymphedema. PMID:28106728

  14. [Pelvic inflammatory disease].

    PubMed

    Hoof, Kathrin

    2007-07-01

    Pelvic inflammatory disease and upper genital tract infection describe inflammatory changes in the upper female genital tract of any combination: endometritis, salpingitis, tubo-ovarian abscess and peritonitis in the small pelvis. In most cases the infection is ascending, Chlamydia trachomatis and Neisseria gonorrhoeae are common with increasing incidence. The spectrum ranges from subclinical, asymptomatic infection to severe, life-threatening illness. Antibiotic treatment should be initiated promptly and must cover a broad spectrum of germs. Surgical treatment is necessary in cases of failure of antibiotic treatment and in cases with persisting symptoms after antibiotic treatment. Pelvic inflammatory diseases are one of the main causes of tubal sterility, ectopic pregnancies and chronic abdominal pain.

  15. Mammalian antimicrobial peptide influences control of cutaneous Leishmania infection

    PubMed Central

    Kulkarni, Manjusha M.; Barbi, Joseph; McMaster, W. Robert; Gallo, Richard L.; Satoskar, Abhay R.; McGwire, Bradford S.

    2011-01-01

    Summary Cathelicidin-type antimicrobial peptides (CAMP) are important mediators of innate immunity against microbial pathogens acting through direct interaction with and disruption of microbial membranes and indirectly through modulation of host cell migration and activation. Using a mouse knock-out model in CAMP we studied the role of this host peptide in control of dissemination of cutaneous infection by the parasitic protozoan Leishmania. The presence of pronounced host inflammatory infiltration in lesions and lymph nodes of infected animals was CAMP-dependent. Lack of CAMP expression was associated with higher levels of IL-10 receptor expression in bone marrow, splenic and lymph node macrophages as well as higher anti-inflammatory IL-10 production by bone marrow macrophages and spleen cells but reduced production of the pro-inflammatory cytokines IL-12 and IFN-γ by lymph nodes. Unlike wild-type mice, local lesions were exacerbated and parasites were found largely disseminated in CAMP knockouts. Infection of CAMP knockouts with parasite mutants lacking the surface metalloprotease virulence determinant resulted in more robust disseminated infection than in control animals suggesting that CAMP activity is negatively regulated by parasite surface proteolytic activity. This correlated with the ability of the pro-tease to degrade CAMP in vitro and co-localization of CAMP with parasites within macrophages. Our results highlight the interplay of antimicrobial peptides and Leishmania that influence the host immune response and the outcome of infection. PMID:21501359

  16. Synthetic cationic peptide IDR-1018 modulates human macrophage differentiation.

    PubMed

    Pena, Olga M; Afacan, Nicole; Pistolic, Jelena; Chen, Carol; Madera, Laurence; Falsafi, Reza; Fjell, Christopher D; Hancock, Robert E W

    2013-01-01

    Macrophages play a critical role in the innate immune response. To respond in a rapid and efficient manner to challenges in the micro-environment, macrophages are able to differentiate towards classically (M1) or alternatively (M2) activated phenotypes. Synthetic, innate defense regulators (IDR) peptides, designed based on natural host defence peptides, have enhanced immunomodulatory activities and reduced toxicity leading to protection in infection and inflammation models that is dependent on innate immune cells like monocytes/macrophages. Here we tested the effect of IDR-1018 on macrophage differentiation, a process essential to macrophage function and the immune response. Using transcriptional, protein and systems biology analysis, we observed that differentiation in the presence of IDR-1018 induced a unique signature of immune responses including the production of specific pro and anti-inflammatory mediators, expression of wound healing associated genes, and increased phagocytosis of apoptotic cells. Transcription factor IRF4 appeared to play an important role in promoting this IDR-1018-induced phenotype. The data suggests that IDR-1018 drives macrophage differentiation towards an intermediate M1-M2 state, enhancing anti-inflammatory functions while maintaining certain pro-inflammatory activities important to the resolution of infection. Synthetic peptides like IDR-1018, which act by modulating the immune system, could represent a powerful new class of therapeutics capable of treating the rising number of multidrug resistant infections as well as disorders associated with dysregulated immune responses.

  17. Synthetic Cationic Peptide IDR-1018 Modulates Human Macrophage Differentiation

    PubMed Central

    Pena, Olga M.; Afacan, Nicole; Pistolic, Jelena; Chen, Carol; Madera, Laurence; Falsafi, Reza; Fjell, Christopher D.; Hancock, Robert E. W.

    2013-01-01

    Macrophages play a critical role in the innate immune response. To respond in a rapid and efficient manner to challenges in the micro-environment, macrophages are able to differentiate towards classically (M1) or alternatively (M2) activated phenotypes. Synthetic, innate defense regulators (IDR) peptides, designed based on natural host defence peptides, have enhanced immunomodulatory activities and reduced toxicity leading to protection in infection and inflammation models that is dependent on innate immune cells like monocytes/macrophages. Here we tested the effect of IDR-1018 on macrophage differentiation, a process essential to macrophage function and the immune response. Using transcriptional, protein and systems biology analysis, we observed that differentiation in the presence of IDR-1018 induced a unique signature of immune responses including the production of specific pro and anti-inflammatory mediators, expression of wound healing associated genes, and increased phagocytosis of apoptotic cells. Transcription factor IRF4 appeared to play an important role in promoting this IDR-1018-induced phenotype. The data suggests that IDR-1018 drives macrophage differentiation towards an intermediate M1–M2 state, enhancing anti-inflammatory functions while maintaining certain pro-inflammatory activities important to the resolution of infection. Synthetic peptides like IDR-1018, which act by modulating the immune system, could represent a powerful new class of therapeutics capable of treating the rising number of multidrug resistant infections as well as disorders associated with dysregulated immune responses. PMID:23308112

  18. Echinometrin: a novel mast cell degranulating peptide from the coelomic liquid of Echinometra lucunter sea urchin.

    PubMed

    Sciani, Juliana Mozer; Sampaio, Marlos Cortez; Zychar, Bianca Cestari; Gonçalves, Luis Roberto de Camargo; Giorgi, Renata; Nogueira, Thiago de Oliveira; de Melo, Robson Lopes; Teixeira, Catarina de Fátima Pereira; Pimenta, Daniel Carvalho

    2014-03-01

    Echinometra lucunter is an abundant sea urchin found in Brazilian waters. Accidents caused by this animal are common and are characterized by the penetration of the spines in the skin, which raises an inflammatory reaction through mechanical trauma as well as by the presumable action of toxins. Additionally, there have been reports of inflammatory reaction after the consumption of raw sea urchin eggs. In this work, we have isolated a peptide from E. lucunter coelomic fluid that could elicit inflammatory reactions, such as paw edema, leukocyte recruitment and diminishment of the pain threshold. This peptide was termed Echinometrin. Moreover, the peptide administration was able to produce in vivo degranulation of mouse mast cells, in a dose-response manner. The peptide was 'de novo' sequenced by mass spectrometry and its synthetic analog could reproduce all the observed effects. Sequence alignment indicates that this peptide is comprised in vitellogenin, an abundant nutrient protein present in the gametogenic cells of sea urchins, making it possible that echinometrin would be a cryptide with pro-inflammatory effects.

  19. Multidimensional signatures in antimicrobial peptides

    PubMed Central

    Yount, Nannette Y.; Yeaman, Michael R.

    2004-01-01

    Conventional analyses distinguish between antimicrobial peptides by differences in amino acid sequence. Yet structural paradigms common to broader classes of these molecules have not been established. The current analyses examined the potential conservation of structural themes in antimicrobial peptides from evolutionarily diverse organisms. Using proteomics, an antimicrobial peptide signature was discovered to integrate stereospecific sequence patterns and a hallmark three-dimensional motif. This striking multidimensional signature is conserved among disulfide-containing antimicrobial peptides spanning biological kingdoms, and it transcends motifs previously limited to defined peptide subclasses. Experimental data validating this model enabled the identification of previously unrecognized antimicrobial activity in peptides of known identity. The multidimensional signature model provides a unifying structural theme in broad classes of antimicrobial peptides, will facilitate discovery of antimicrobial peptides as yet unknown, and offers insights into the evolution of molecular determinants in these and related host defense effector molecules. PMID:15118082

  20. Vasculitis and inflammatory arthritis.

    PubMed

    Watts, Richard A; Scott, David G I

    2016-10-01

    Vasculitis has been described in most types of inflammatory arthritis. The best described and most widely recognised form is rheumatoid vasculitis. The incidence of systemic rheumatoid vasculitis has declined significantly following the general early use of methotrexate in the 1990s, and it is now a rare form of vasculitis. Treatment of rheumatoid vasculitis is conventionally with glucocorticoids and cyclophosphamide, but there is an increasing role for rituximab similar to that in other types of vasculitis. Despite these developments the mortality of rheumatoid vasculitis remains high. Vasculitis in other types of inflammatory arthritis is less well described and the treatment remains empirical. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Acquired inflammatory demyelinating neuropathies.

    PubMed

    Ensrud, E R; Krivickas, L S

    2001-05-01

    The acquired demyelinating neuropathies can be divided into those with an acute onset and course and those with a more chronic course. The acute neuropathies present as Guillain-Barré syndrome and include acute inflammatory demyelinating polyradiculoneuropathy (AIDP), Miller Fisher syndrome, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), and acute pandysautonomia. The chronic neuropathies are collectively known as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and include MADSAM (multifocal acquired demyelinating sensory and motor neuropathy, also know as Lewis-Sumner syndrome) and DADS (distal acquired demyelinating symmetric neuropathy) as variants. The clinical features, pathology, pathogenesis, diagnosis, treatment, rehabilitation, and prognosis of these neuropathies are discussed.

  2. Related impurities in peptide medicines.

    PubMed

    D'Hondt, Matthias; Bracke, Nathalie; Taevernier, Lien; Gevaert, Bert; Verbeke, Frederick; Wynendaele, Evelien; De Spiegeleer, Bart

    2014-12-01

    Peptides are an increasingly important group of pharmaceuticals, positioned between classic small organic molecules and larger bio-molecules such as proteins. Currently, the peptide drug market is growing twice as fast as other drug markets, illustrating the increasing clinical as well as economical impact of this medicine group. Most peptides today are manufactured by solid-phase peptide synthesis (SPPS). This review will provide a structured overview of the most commonly observed peptide-related impurities in peptide medicines, encompassing the active pharmaceutical ingredients (API or drug substance) as well as the finished drug products. Not only is control of these peptide-related impurities and degradants critical for the already approved and clinically used peptide-drugs, these impurities also possess the capability of greatly influencing initial functionality studies during early drug discovery phases, possibly resulting in erroneous conclusions. The first group of peptide-related impurities is SPPS-related: deletion and insertion of amino acids are related to inefficient Fmoc-deprotection and excess use of amino acid reagents, respectively. Fmoc-deprotection can cause racemization of amino acid residues and thus diastereomeric impurities. Inefficient deprotection of amino acid side chains results into peptide-protection adducts. Furthermore, unprotected side chains can react with a variety of reagents used in the synthesis. Oxidation of amino acid side chains and dimeric-to-oligomeric impurities were also observed. Unwanted peptide counter ions such as trifluoroacetate, originating from the SPPS itself or from additional purification treatments, may also be present in the final peptide product. Contamination of the desired peptide product by other unrelated peptides was also seen, pointing out the lack of appropriate GMP. The second impurity group results from typical peptide degradation mechanisms such as β-elimination, diketopiperazine, pyroglutamate

  3. Brain Peptides and Psychopharmacology

    ERIC Educational Resources Information Center

    Arehart-Treichel, Joan

    1976-01-01

    Proteins isolated from the brain and used as drugs can improve and apparently even transfer mental states and behavior. Much of the pioneering work and recent research with humans and animals is reviewed and crucial questions that are being posed about the psychologically active peptides are related. (BT)

  4. Peptide -- Silica Hybrid Networks

    NASA Astrophysics Data System (ADS)

    Altunbas, Aysegul; Sharma, Nikhil; Nagarkar, Radhika; Schneider, Joel; Pochan, Darrin

    2010-03-01

    In this study, a bio-inspired route was used to fabricate scaffolds that display hierarchical organization of an inorganic layer around an organic self-assembled peptide fibril template. The 20 amino acid peptide used in this study intramolecular folds into a beta-hairpin conformation on addition of a desired solution stimulus. This intramolecular folding is followed by intermolecular self-assembly of the peptides into a three dimensional network of entangled fibrils rich in beta-sheet with a high density of lysine groups exposed on the fibril-surfaces. The lysine-rich surface chemistry was utilized to create a silica shell around the fibrils. The mineralization process of the fibrils results in a rigid, porous silica network that retains the microscale and nanoscale structure of the peptide fibril network. Structural characterization via Transmission Electron Microscopy, cryogenic-Scanning Electron Microscopy, mechanical characterization via oscillatory rheology, Small Angle X-ray and Neutron Scattering of the silicified hydrogels will be presented.

  5. Bioinformatic identification of plant peptides.

    PubMed

    Lease, Kevin A; Walker, John C

    2010-01-01

    Plant peptides play a number of important roles in defence, development and many other aspects of plant physiology. Identifying additional peptide sequences provides the starting point to investigate their function using molecular, genetic or biochemical techniques. Due to their small size, identifying peptide sequences may not succeed using the default bioinformatic approaches that work well for average-sized proteins. There are two general scenarios related to bioinformatic identification of peptides to be discussed in this paper. In the first scenario, one already has the sequence of a plant peptide and is trying to find more plant peptides with some sequence similarity to the starting peptide. To do this, the Basic Local Alignment Search Tool (BLAST) is employed, with the parameters adjusted to be more favourable for identifying potential peptide matches. A second scenario involves trying to identify plant peptides without using sequence similarity searches to known plant peptides. In this approach, features such as protein size and the presence of a cleavable amino-terminal signal peptide are used to screen annotated proteins. A variation of this method can be used to screen for unannotated peptides from genomic sequences. Bioinformatic resources related to Arabidopsis thaliana will be used to illustrate these approaches.

  6. Hypoglycemic agents and potential anti-inflammatory activity

    PubMed Central

    Kothari, Vishal; Galdo, John A; Mathews, Suresh T

    2016-01-01

    Current literature shows an association of diabetes and secondary complications with chronic inflammation. Evidence of these immunological changes include altered levels of cytokines and chemokines, changes in the numbers and activation states of various leukocyte populations, apoptosis, and fibrosis during diabetes. Therefore, treatment of diabetes and its complications may include pharmacological strategies to reduce inflammation. Apart from anti-inflammatory drugs, various hypoglycemic agents have also been found to reduce inflammation that could contribute to improved outcomes. Extensive studies have been carried out with thiazolidinediones (peroxisome proliferator-activated receptor-γ agonist), dipeptidyl peptidase-4 inhibitors, and metformin (AMP-activated protein kinase activator) with each of these classes of compounds showing moderate-to-strong anti-inflammatory action. Sulfonylureas and alpha glucosidase inhibitors appeared to exert modest effects, while the injectable agents, insulin and glucagon-like peptide-1 receptor agonists, may improve secondary complications due to their anti-inflammatory potential. Currently, there is a lack of clinical data on anti-inflammatory effects of sodium–glucose cotransporter type 2 inhibitors. Nevertheless, for all these glucose-lowering agents, it is essential to distinguish between anti-inflammatory effects resulting from better glucose control and effects related to intrinsic anti-inflammatory actions of the pharmacological class of compounds. PMID:27114714

  7. Neutrophil secretion products pave the way for inflammatory monocytes.

    PubMed

    Soehnlein, Oliver; Zernecke, Alma; Eriksson, Einar E; Rothfuchs, Antonio Gigliotti; Pham, Christine T; Herwald, Heiko; Bidzhekov, Kiril; Rottenberg, Martin E; Weber, Christian; Lindbom, Lennart

    2008-08-15

    The leukocyte response in inflammation is characterized by an initial recruitment of polymorphonuclear leukocytes (PMN) preceding a second wave of monocytes to the site of injury or infection. In the mouse, 2 populations of monocytes have been identified, Gr1(-)CCR2(-)CX3CR1(hi) resident monocytes and Gr1(+)CCR2(+)CX3CR1(lo) inflammatory monocytes. Here, intravital microscopy of the musculus cremaster and a subcutaneous air pouch model were used to investigate a possible link between PMN extravasation and the subsequent emigration of inflammatory monocytes in response to local stimulation with PAF. In mice that were made neutropenic by injection of a PMN-depleting antibody, the extravasation of inflammatory monocytes, but not resident monocytes, was markedly reduced compared with mice with intact white blood cell count but was restored by local treatment with secretion of activated PMN. Components of the PMN secretion were found to directly activate inflammatory monocytes and further examination revealed PMN-derived LL-37 and heparin-binding protein (HBP/CAP37/azurocidin) as primary mediators of the recruitment of inflammatory monocytes via activation of formyl-peptide receptors. These data show that LL-37 and HBP specifically stimulate mobilization of inflammatory monocytes. This cellular cross-talk functionally results in enhanced cytokine levels and increased bacterial clearance, thus boosting the early immune response.

  8. Mucins and inflammatory bowel disease

    PubMed Central

    Shirazi, T.; Longman, R.; Corfield, A.; Probert, C.

    2000-01-01

    There is a layer of mucus lining the gastrointestinal tract, which acts as both a lubricant and as a physical barrier between luminal contents and the mucosal surface. The mucins that make up this layer consist of a protein backbone with oligosaccharides attached to specific areas of the protein core. These areas are called the variable number tandem repeat regions. The degree of glycosylation of the mucins is central to their role in the mucus barrier. The oligosaccharides are variable and complex. It has been demonstrated that the degree of sulphation and sialylation and the length of the oligosaccharide chains all vary in inflammatory bowel disease. These changes can alter the function of the mucins. Mucins are broadly divided into two groups, those that are secreted and those that are membrane bound. The major mucins present in the colorectum are MUC1, MUC2, MUC3, and MUC4.
Trefoils are a group of small peptides that have an important role in the mucus layer. Three trefoils have been demonstrated so far. They seem to play a part in mucosal protection and in mucosal repair. They may help to stabilise the mucus layer by cross linking with mucins to aid formation of stable gels. Trefoils can be expressed in the ulcer associated cell lineage, a glandular structure that can occur in the inflamed mucosa. There seem to be differences in the expression of trefoils in the colon and the small bowel, which may imply different method of mucosal repair.


Keywords: mucins; trefoil; Crohn's disease; colitis PMID:10908374

  9. Synthesis of peptide analogues using the multipin peptide synthesis method.

    PubMed

    Valerio, R M; Benstead, M; Bray, A M; Campbell, R A; Maeji, N J

    1991-08-15

    Modification of the multipin peptide synthesis method which allows the simultaneous synthesis of large numbers of different peptide analogues is described. Peptides were assembled on polyethylene pins derivatized with a 4-(beta-alanyloxymethyl)benzoate (beta-Ala-HMB) handle. For comparative purposes, peptides were also assembled on the diketopiperazine-forming handle N epsilon-(beta-alanyl)lysylprolyloxylactate. In model studies it was demonstrated that beta-Ala-HMB-linked peptides were cleaved from polyethylene pins with dilute sodium hydroxide or 4% methylamine/water to yield analogues with beta-Ala-free acid (beta-Ala-CO2H) and beta-Ala-methylamide (beta-Ala-CONHCH3), respectively. To assess the suitability of this approach for T-cell determinant analysis, analogues of a known T-cell determinant were synthesized with the various C-terminal endings. Peptides were characterized by amino acid analysis and fast atom bombardment-mass spectrometry. HPLC of the crude cleaved peptides indicated that 22 of the 24 peptides were greater than 95% pure. These crude peptide solutions were nontoxic in sensitive cell culture assays without further purification. All three cleavage procedures gave comparable activities in T-cell proliferation assays. These results demonstrate the potential of the multipin peptide synthesis method for the production of large numbers of different peptide analogues.

  10. Biochemical functionalization of peptide nanotubes with phage displayed peptides

    NASA Astrophysics Data System (ADS)

    Swaminathan, Swathi; Cui, Yue

    2016-09-01

    The development of a general approach for the biochemical functionalization of peptide nanotubes (PNTs) could open up existing opportunities in both fundamental studies as well as a variety of applications. PNTs are spontaneously assembled organic nanostructures made from peptides. Phage display has emerged as a powerful approach for identifying selective peptide binding motifs. Here, we demonstrate for the first time the biochemical functionalization of PNTs via peptides identified from a phage display peptide library. The phage-displayed peptides are shown to recognize PNTs. These advances further allow for the development of bifunctional peptides for the capture of bacteria and the self-assembly of silver particles onto PNTs. We anticipate that these results could provide significant opportunities for using PNTs in both fundamental studies and practical applications, including sensors and biosensors nanoelectronics, energy storage devices, drug delivery, and tissue engineering.

  11. Pelvic inflammatory disease

    PubMed Central

    2013-01-01

    Introduction Pelvic inflammatory disease is caused by infection of the upper female genital tract and is often asymptomatic. Pelvic inflammatory disease is the most common gynaecological reason for admission to hospital in the US, and is diagnosed in approximately 1% of women aged 16 to 45 years consulting their GP in England and Wales. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: How do different antimicrobial regimens compare when treating women with confirmed pelvic inflammatory disease? What are the effects of routine antibiotic prophylaxis to prevent pelvic inflammatory disease before intrauterine contraceptive device (IUD) insertion? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 13 RCTs or systematic reviews of RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review, we present information relating to the effectiveness and safety of the following interventions: antibiotics (oral, parenteral, different durations, different regimens) and routine antibiotic prophylaxis (before intrauterine device insertion in women at high risk or low risk). PMID:24330771

  12. Pelvic inflammatory disease.

    PubMed

    Ross, Jonathan D C

    2013-12-11

    Pelvic inflammatory disease is caused by infection of the upper female genital tract and is often asymptomatic. Pelvic inflammatory disease is the most common gynaecological reason for admission to hospital in the US, and is diagnosed in approximately 1% of women aged 16 to 45 years consulting their GP in England and Wales. We conducted a systematic review and aimed to answer the following clinical questions: How do different antimicrobial regimens compare when treating women with confirmed pelvic inflammatory disease? What are the effects of routine antibiotic prophylaxis to prevent pelvic inflammatory disease before intrauterine contraceptive device (IUD) insertion? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 13 RCTs or systematic reviews of RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review, we present information relating to the effectiveness and safety of the following interventions: antibiotics (oral, parenteral, different durations, different regimens) and routine antibiotic prophylaxis (before intrauterine device insertion in women at high risk or low risk).

  13. Prostacyclin: An Inflammatory Paradox

    PubMed Central

    Stitham, Jeremiah; Midgett, Charles; Martin, Kathleen A.; Hwa, John

    2011-01-01

    Prostacyclin (PGI2) is a member of the prostaglandin family of bioactive lipids. Its best-characterized role is in the cardiovascular system, where it is released by vascular endothelial cells, serving as a potent vasodilator and inhibitor of platelet aggregation. In recent years, prostacyclin (PGI2) has also been shown to promote differentiation and inhibit proliferation in vascular smooth muscle cells. In addition to these well-described homeostatic roles within the cardiovascular system, prostacyclin (PGI2) also plays an important role as an inflammatory mediator. In this review, we focus on the contribution of prostacyclin (PGI2) as both a pathophysiological mediator and therapeutic agent in three major inflammatory-mediated disease processes, namely rheumatoid arthritis, where it promotes disease progression (“pro-inflammatory”), along with pulmonary vascular disease and atherosclerosis, where it inhibits disease progression (“anti-inflammatory”). The emerging role of prostacyclin (PGI2) in this context provides new opportunities for understanding the complex molecular basis for inflammatory-related diseases, and insights into the development of current and future anti-inflammatory treatments. PMID:21687516

  14. Proteins and peptides: The need to improve them as promising therapeutics for ulcerative colitis.

    PubMed

    Sahu, Kantrol Kumar; Minz, Sunita; Kaurav, Monika; Pandey, Ravi Shankar

    2016-01-01

    The present review briefly describes the nature, type and pathogenesis of ulcerative colitis, and explores the potential use of peptides and proteins in the treatment of inflammatory bowel disease, especially ulcerative colitis. Intestinal absorption and the barrier mechanism of peptide and protein drugs are also discussed, with special emphasis on various strategies which make these drugs better therapeutics having high specificity, potency and molecular targeting ability. However, the limitation of such therapeutics are oral administration, poor pharmacokinetic profile and decreased bioavailability. The recent findings illustrated in this review will be helpful in designing the peptide/protein drugs as a promising treatment of choice for ulcerative colitis.

  15. Development of bioactive peptides from fish proteins and their health promoting ability.

    PubMed

    Senevirathne, Mahinda; Kim, Se-Kwon

    2012-01-01

    Great amount of marine fish species have been identified with potential nutraceutical and medicinal values. Consequently, a number of bioactive compounds have been identified including fish muscle proteins, peptides, collagen and gelatin, fish oil, fish bone. Bioactive peptides derived from various fish muscle proteins have shown various biological activities including antihypertensive, antibacterial, anticoagulant, anti-inflammatory, and antioxidant activities, and hence they may be a potential material for biomedical and food industries. Further, they are commonly used in medical and pharmaceutical industries as carrier molecules for drugs, proteins, and genes. Hence, fish muscle protein-derived peptides are valuable natural resources that can be potential material for biomedical, nutraceutical, and food industries.

  16. A Peptide Filtering Relation Quantifies MHC Class I Peptide Optimization

    PubMed Central

    Goldstein, Leonard D.; Howarth, Mark; Cardelli, Luca; Emmott, Stephen; Elliott, Tim; Werner, Joern M.

    2011-01-01

    Major Histocompatibility Complex (MHC) class I molecules enable cytotoxic T lymphocytes to destroy virus-infected or cancerous cells, thereby preventing disease progression. MHC class I molecules provide a snapshot of the contents of a cell by binding to protein fragments arising from intracellular protein turnover and presenting these fragments at the cell surface. Competing fragments (peptides) are selected for cell-surface presentation on the basis of their ability to form a stable complex with MHC class I, by a process known as peptide optimization. A better understanding of the optimization process is important for our understanding of immunodominance, the predominance of some T lymphocyte specificities over others, which can determine the efficacy of an immune response, the danger of immune evasion, and the success of vaccination strategies. In this paper we present a dynamical systems model of peptide optimization by MHC class I. We incorporate the chaperone molecule tapasin, which has been shown to enhance peptide optimization to different extents for different MHC class I alleles. Using a combination of published and novel experimental data to parameterize the model, we arrive at a relation of peptide filtering, which quantifies peptide optimization as a function of peptide supply and peptide unbinding rates. From this relation, we find that tapasin enhances peptide unbinding to improve peptide optimization without significantly delaying the transit of MHC to the cell surface, and differences in peptide optimization across MHC class I alleles can be explained by allele-specific differences in peptide binding. Importantly, our filtering relation may be used to dynamically predict the cell surface abundance of any number of competing peptides by MHC class I alleles, providing a quantitative basis to investigate viral infection or disease at the cellular level. We exemplify this by simulating optimization of the distribution of peptides derived from Human

  17. Unfulfilled inflammatory resolution leads to chronic inflammatory diseases.

    PubMed

    Musk, Philip

    2004-06-01

    Extract: Inflammatory conditions, particularly those that involve chronic inflammation, represent an area of great interest to the pharmaceutical industry. Regulated as they are by a diverse array of ligand-receptor interactions, inflammatory responses are amenable to small molecule pharmaceutical intervention and a wide variety of anti-histamines and anti-inflammatory treatments. Both steroidal and non-steroidal treatments have been developed to treat pro-inflammatory conditions. In their review, Gilroy et al. (2004) present the case for developing novel anti-inflammatory drugs not by finding more effective inhibitors of the inflammatory response, but by developing small molecule drugs that positively regulate the processes and mechanisms by which inflammatory responses are attenuated (i.e., the little known process of inflammatory resolution).

  18. Characterization of a new bioactive peptide from Potamotrygon gr. orbignyi freshwater stingray venom.

    PubMed

    Conceição, Katia; Santos, Juliane M; Bruni, Fernanda M; Klitzke, Clécio F; Marques, Elineide E; Borges, Márcia H; Melo, Robson L; Fernandez, Jorge H; Lopes-Ferreira, Mônica

    2009-12-01

    Brazilian freshwater stingrays, Potamotrygon gr. orbigyni, are relatively common in the middle-western regions of Brazil, where they are considered an important public health threat. In order to identify some of their naturally occurring toxin peptides available in very low amounts, we combine analytical protocols such as reversed-phase high-performance liquid chromatography (RP-HPLC), followed by a biological microcirculatory screening and mass spectrometry analysis. Using this approach, one bioactive peptide was identified and characterized, and two analogues were synthesized. The natural peptide named Porflan has the primary structure ESIVRPPPVEAKVEETPE (MW 2006.09 Da) and has no similarity with any bioactive peptide or protein found in public data banks. Bioassay protocols characterized peptides as presenting potent activity in a microcirculatory environment. The primary sequences and bioassay results, including interactions with the membrane phospholipids, suggest that these toxins are a new class of fish toxins, directly involved in the inflammatory processes of a stingray sting.

  19. Egg-derived bioactive peptides with ACE-inhibitory properties: a literature update.

    PubMed

    Grootaert, Charlotte; Matthijs, Bea; Voorspoels, Stefan; Possemiers, Sam; Smagghe, Guy; Van Camp, John

    2017-09-25

    Egg proteins contain a wide set of peptide sequences which have an impact on cardiovascular health. Their modes-of-action involve, among others, the inhibition of angiotensin-converting enzyme (ACE) and antioxidant and anti-inflammatory properties. In this review, we focus particularly on ACE-inhibition and discuss recent findings in: (i) production methods for egg protein-derived ACE-inhibitory peptides, (ii) in vitro functionality of these peptides, (iii) their intestinal digestion and absorption in order to reach the target tissue, (iv) the impact of ACE-inhibitory egg-derived peptides in vivo and (v) future perspectives for the implementation of egg-derived ACE-inhibitory peptides as functional foods.

  20. Inflammatory prostaglandin E2 signaling in a mouse model of Alzheimer’s disease

    PubMed Central

    Shi, Ju; Wang, Qian; Johansson, Jenny U.; Liang, Xibin; Woodling, Nathaniel S.; Priyam, Prachi; Loui, Taylor M.; Merchant, Milton; Breyer, Richard M.; Montine, Thomas J.; Andreasson, Katrin

    2012-01-01

    Objective There is significant evidence for a central role of inflammation in the development of Alzheimer’s disease (AD). Epidemiological studies indicate that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD in healthy aging populations. As NSAIDs inhibit the enzymatic activity of the inflammatory cyclooxygenases COX-1 and COX-2, these findings suggest that downstream prostaglandin signaling pathways function in the pre-clinical development of AD. Here, we investigate the function of prostaglandin E2 (PGE2) signaling through its EP3 receptor in the neuroinflammatory response to Aβ peptide. Methods The function of PGE2 signaling through its EP3 receptor was examined in vivo a model of subacute neuroinflammation induced by administration of Aβ42 peptides. Our findings were then confirmed in young adult APPSwe-PS1 ΔE9 transgenic mice. Results Deletion of the PGE2 EP3 receptor in a model of Aβ42 peptide-induced neuroinflammation reduced pro-inflammatory gene expression, cytokine production, and oxidative stress. In the APPSwe-PS1 ΔE9 model of Familial AD, deletion of the EP3 receptor blocked induction of pro-inflammatory gene and protein expression and lipid peroxidation. In addition, levels of Aβ peptides were significantly decreased, as were BACE-1 and β-CTF levels, suggesting that generation of Aβ peptides may be increased as a result of pro-inflammatory EP3 signaling. Finally, deletion of EP3 receptor significantly reversed the decline in pre-synaptic proteins seen in APPSwe-PS1 ΔE9 mice. Interpretation Our findings identify the PGE2 EP3 receptor as a novel pro-inflammatory, pro-amyloidogenic, and synaptotoxic signaling pathway, and suggest a role for COX-PGE2-EP3 signaling in the development of AD. PMID:22915243

  1. LC-MS/MS Identification of a Bromelain Peptide Biomarker from Ananas comosus Merr

    PubMed Central

    Secor, Eric R.; Szczepanek, Steven M.; Singh, Anurag; Guernsey, Linda; Natarajan, Prabitha; Rezaul, Karim; Han, David K.; Thrall, Roger S.; Silbart, Lawrence K.

    2012-01-01

    Bromelain (Br) is a cysteine peptidase (GenBank AEH26024.1) from pineapple, with over 40 years of clinical use. The constituents mediating its anti-inflammatory activity are not thoroughly characterized and no peptide biomarker exists. Our objective is to characterize Br raw material and identify peptides in the plasma of Br treated mice. After SDS-PAGE in-gel digestion, Br (VN#3507; Middletown, CT, USA) peptides were analyzed via LC/MS/MS using 95% protein probability, 95% peptide probability, and a minimum peptide number = 5. Br spiked mouse plasma (1 ug/ul) and plasma from i.p. treated mice (12 mg/kg) were assessed using SRM. In Br raw material, we identified seven proteins: four proteases, one jacalin-like lectin, and two protease inhibitors. In Br spiked mouse plasma, six proteins (ananain, bromelain inhibitor, cysteine proteinase AN11, FB1035 precursor, FBSB precursor, and jacalin-like lectin) were identified. Using LC/MS/MS, we identified the unique peptide, DYGAVNEVK, derived from FB1035, in the plasma of i.p. Br treated mice. The spectral count of this peptide peaked at 6 hrs and was undetectable by 24 hrs. In this study, a novel Br peptide was identified in the plasma of treated mice for the first time. This Br peptide could serve as a biomarker to standardize the therapeutic dose and maximize clinical utility. PMID:23082082

  2. LC-MS/MS Identification of a Bromelain Peptide Biomarker from Ananas comosus Merr.

    PubMed

    Secor, Eric R; Szczepanek, Steven M; Singh, Anurag; Guernsey, Linda; Natarajan, Prabitha; Rezaul, Karim; Han, David K; Thrall, Roger S; Silbart, Lawrence K

    2012-01-01

    Bromelain (Br) is a cysteine peptidase (GenBank AEH26024.1) from pineapple, with over 40 years of clinical use. The constituents mediating its anti-inflammatory activity are not thoroughly characterized and no peptide biomarker exists. Our objective is to characterize Br raw material and identify peptides in the plasma of Br treated mice. After SDS-PAGE in-gel digestion, Br (VN#3507; Middletown, CT, USA) peptides were analyzed via LC/MS/MS using 95% protein probability, 95% peptide probability, and a minimum peptide number = 5. Br spiked mouse plasma (1 ug/ul) and plasma from i.p. treated mice (12 mg/kg) were assessed using SRM. In Br raw material, we identified seven proteins: four proteases, one jacalin-like lectin, and two protease inhibitors. In Br spiked mouse plasma, six proteins (ananain, bromelain inhibitor, cysteine proteinase AN11, FB1035 precursor, FBSB precursor, and jacalin-like lectin) were identified. Using LC/MS/MS, we identified the unique peptide, DYGAVNEVK, derived from FB1035, in the plasma of i.p. Br treated mice. The spectral count of this peptide peaked at 6 hrs and was undetectable by 24 hrs. In this study, a novel Br peptide was identified in the plasma of treated mice for the first time. This Br peptide could serve as a biomarker to standardize the therapeutic dose and maximize clinical utility.

  3. Concepts for Biologically Active Peptides

    PubMed Central

    Kastin, Abba J.; Pan, Weihong

    2012-01-01

    Here we review a unique aspect of CNS research on biologically active peptides that started against a background of prevalent dogmas but ended by exerting considerable influence on the field. During the course of refuting some doctrines, we introduced several concepts that were unconventional and paradigm-shifting at the time. We showed that (1) hypothalamic peptides can act ‘up’ on the brain as well as ‘down’ on the pituitary, (2) peripheral peptides can affect the brain, (3) peptides can cross the blood-brain barrier, (4) the actions of peptides can persist longer than their half-lives in blood, (5) perinatal administration of peptides can exert actions persisting into adulthood, (6) a single peptide can have more than one action, (7) dose-response relationships of peptides need not be linear, (8) the brain produces antiopiate as well as opiate peptides, (9) there is a selective high affinity endogenous peptide ligand for the mu-opiate receptor, (10) a peptide’s name does not restrict its effects, and (11) astrocytes assume an active role in response to metabolic disturbance and hyperleptinemia. The evolving questions in our laboratories reflect the diligent effort of the neuropeptide community to identify the roles of peptides in the CNS. The next decade is expected to see greater progress in the following areas: (a) interactions of peptides with other molecules in the CNS; (b) peptide involvement in cell-cell interactions; and (c) peptides in neuropsychiatric, autoimmune, and neurodegenerative diseases. The development of peptidomics and gene silencing approaches will expedite the formation of many new concepts in a new era. PMID:20726835

  4. Commensal-Epithelial Signaling Mediated via Formyl Peptide Receptors

    PubMed Central

    Wentworth, Christy C.; Jones, Rheinallt M.; Kwon, Young Man; Nusrat, Asma; Neish, Andrew S.

    2010-01-01

    Commensal bacteria and/or their products engender beneficial effects to the mammalian gut, including stimulating physiological cellular turnover and enhancing wound healing, without activating overt inflammation. In the present study, we observed commensal bacteria-mediated activation of the noninflammatory extracellular signal-regulated kinase[ERK]/mitogen-activated protein kinase and Akt signaling pathways in gut epithelial cells and delineated a mechanism for this bacterially activated signaling. All tested strains of commensal bacteria induced ERK phosphorylation without stimulating pro-inflammatory phospho-IκB or pro-apoptotic phospho-c-Jun NH2-terminal kinase, with Lactobacillus species being most potent. This pattern of signaling activation was recapitulated using the peptide N-formyl-Met-Leu-Phe, a bacterial product known to stimulate signaling events in mammalian phagocytes. Sensing of N-formyl-Met-Leu-Phe by gut epithelial cells occurs via recently characterized formyl peptide receptors located in the plasma membrane. Both commensal bacteria and N-formyl-Met-Leu-Phe application to the apical surface of polarized gut epithelial cells resulted in specific formyl peptide receptor activation. In addition, pretreatment of model epithelia and murine colon with Boc2 (a specific peptide antagonist) or pertussis toxin (a Gi-protein inhibitor) abolished commensal-mediated ERK phosphorylation. Taken together, these data show that commensal bacteria specifically activate the ERK/mitogen-activated protein kinase pathway in an formyl peptide receptor-dependent manner, delineating a mechanism by which commensal bacteria contribute to cellular signaling in gut epithelia. PMID:21037077

  5. Commensal-epithelial signaling mediated via formyl peptide receptors.

    PubMed

    Wentworth, Christy C; Jones, Rheinallt M; Kwon, Young Man; Nusrat, Asma; Neish, Andrew S

    2010-12-01

    Commensal bacteria and/or their products engender beneficial effects to the mammalian gut, including stimulating physiological cellular turnover and enhancing wound healing, without activating overt inflammation. In the present study, we observed commensal bacteria-mediated activation of the noninflammatory extracellular signal-regulated kinase[ERK]/mitogen-activated protein kinase and Akt signaling pathways in gut epithelial cells and delineated a mechanism for this bacterially activated signaling. All tested strains of commensal bacteria induced ERK phosphorylation without stimulating pro-inflammatory phospho-IκB or pro-apoptotic phospho-c-Jun NH(2)-terminal kinase, with Lactobacillus species being most potent. This pattern of signaling activation was recapitulated using the peptide N-formyl-Met-Leu-Phe, a bacterial product known to stimulate signaling events in mammalian phagocytes. Sensing of N-formyl-Met-Leu-Phe by gut epithelial cells occurs via recently characterized formyl peptide receptors located in the plasma membrane. Both commensal bacteria and N-formyl-Met-Leu-Phe application to the apical surface of polarized gut epithelial cells resulted in specific formyl peptide receptor activation. In addition, pretreatment of model epithelia and murine colon with Boc2 (a specific peptide antagonist) or pertussis toxin (a G(i)-protein inhibitor) abolished commensal-mediated ERK phosphorylation. Taken together, these data show that commensal bacteria specifically activate the ERK/mitogen-activated protein kinase pathway in an formyl peptide receptor-dependent manner, delineating a mechanism by which commensal bacteria contribute to cellular signaling in gut epithelia.

  6. Adrenomedullin - new perspectives of a potent peptide hormone.

    PubMed

    Schönauer, Ria; Els-Heindl, Sylvia; Beck-Sickinger, Annette G

    2017-07-01

    Adrenomedullin (ADM) is a 52-amino acid multifunctional peptide, which belongs to the calcitonin gene-related peptide (CGRP) superfamily of vasoactive peptide hormones. ADM exhibits a significant vasodilatory potential and plays a key role in various regulatory mechanisms, predominantly in the cardiovascular and lymphatic system. It exerts its effects by activation of the calcitonin receptor-like receptor associated with one of the receptor activity-modifying proteins 2 or 3. ADM was first isolated from human phaeochromocytoma in 1993. Numerous studies revealed a widespread distribution in various tissues and organs, which is reflected by its multiple physiological roles in health and disease. Because of its anti-inflammatory, anti-apoptotic and proliferative properties, ADM exhibits potent protective functions under diverse pathological conditions, but it is also critically involved in tumor progression. ADM has therefore raised great interest in therapeutic applications and several clinical trials already revealed promising results. However, because the receptor activation mode has not yet been fully elucidated, a rational design of potent and selective ligands is still challenging. Detailed information on the binding mode of ADM from a recently reported crystal structure as well as efforts to improve its plasma stability and bioavailability may help to overcome these limitations in the future. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

  7. Engineered knottin peptides as diagnostics, therapeutics, and drug delivery vehicles.

    PubMed

    Kintzing, James R; Cochran, Jennifer R

    2016-10-01

    Inhibitor cystine-knots, also known as knottins, are a structural family of ultra-stable peptides with diverse functions. Knottins and related backbone-cyclized peptides called cyclotides contain three disulfide bonds connected in a particular arrangement that endows these peptides with high thermal, proteolytic, and chemical stability. Knottins have gained interest as candidates for non-invasive molecular imaging and for drug development as they can possess the pharmacological properties of small molecules and the target affinity and selectively of protein biologics. Naturally occurring knottins are clinically approved for treating chronic pain and GI disorders. Combinatorial methods are being used to engineer knottins that can bind to other clinically relevant targets in cancer, and inflammatory and cardiac disease. This review details recent examples of engineered knottin peptides; their use as molecular imaging agents, therapeutics, and drug delivery vehicles; modifications that can be introduced to improve peptide folding and bioactivity; and future perspectives and challenges in the field. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Electron capture dissociation mass spectrometry of tyrosine nitrated peptides.

    PubMed

    Jones, Andrew W; Mikhailov, Victor A; Iniesta, Jesus; Cooper, Helen J

    2010-02-01

    In vivo protein nitration is associated with many disease conditions that involve oxidative stress and inflammatory response. The modification involves addition of a nitro group at the position ortho to the phenol group of tyrosine to give 3-nitrotyrosine. To understand the mechanisms and consequences of protein nitration, it is necessary to develop methods for identification of nitrotyrosine-containing proteins and localization of the sites of modification. Here, we have investigated the electron capture dissociation (ECD) and collision-induced dissociation (CID) behavior of 3-nitrotyrosine-containing peptides. The presence of nitration did not affect the CID behavior of the peptides. For the doubly-charged peptides, addition of nitration severely inhibited the production of ECD sequence fragments. However, ECD of the triply-charged nitrated peptides resulted in some singly-charged sequence fragments. ECD of the nitrated peptides is characterized by multiple losses of small neutral species including hydroxyl radicals, water and ammonia. The origin of the neutral losses has been investigated by use of activated ion (AI) ECD. Loss of ammonia appears to be the result of non-covalent interactions between the nitro group and protonated lysine side-chains.

  9. The emerging role of peptides and lipids as antimicrobial epidermal barriers and modulators of local inflammation

    PubMed Central

    Brogden, N.K.; Mehalick, L.; Fischer, C.L.; Wertz, P.W.; Brogden, K.A.

    2012-01-01

    Skin is complex and comprised of distinct layers, each layer with unique architecture and immunologic functions. Cells within these layers produce differing amounts of antimicrobial peptides and lipids (sphingoid bases and sebaceous fatty acids) that limit colonization of commensal and opportunistic microorganisms. Furthermore, antimicrobial peptides and lipids have distinct, concentration-dependent ancillary innate and adaptive immune functions. At 0.1-2.0 μM, antimicrobial peptides induce cell migration and adaptive immune responses to co-administered antigens. At 2.0-6.0 μM, they induce cell proliferation and enhance wound healing. At 6.0-12.0 μM, antimicrobial peptides can regulate chemokine and cytokine production and at their highest concentrations of 15.0-30.0 μM, antimicrobial peptides can be cytotoxic. At 1-100 nM, lipids enhance cell migration induced by chemokines, suppress apoptosis, and optimize T cell cytotoxicity and at 0.3-1.0 μM, they inhibit cell migration and attenuate chemokine and pro-inflammatory cytokine responses. Recently many antimicrobial peptides and lipids at 0.1-2.0 μM have been found to attenuate the production of chemokines and pro-inflammatory cytokines to microbial antigens. Together, both the antimicrobial and the anti-inflammatory activities of these peptides and lipids may serve to create a strong, overlapping immunologic barrier that not only controls the concentrations of cutaneous commensal flora but also the extent to which they induce a localized inflammatory response. PMID:22538862

  10. The Role of Formylated Peptides and Formyl Peptide Receptor 1 in Governing Neutrophil Function during Acute Inflammation

    PubMed Central

    Dorward, David A.; Lucas, Christopher D.; Chapman, Gavin B.; Haslett, Christopher; Dhaliwal, Kevin; Rossi, Adriano G.

    2015-01-01

    Neutrophil migration to sites of inflammation and the subsequent execution of multiple functions are designed to contain and kill invading pathogens. These highly regulated and orchestrated processes are controlled by interactions between numerous receptors and their cognate ligands. Unraveling and identifying those that are central to inflammatory processes may represent novel therapeutic targets for the treatment of neutrophil-dominant inflammatory disorders in which dysregulated neutrophil recruitment, function, and elimination serve to potentiate rather than resolve an initial inflammatory insult. The first G protein–coupled receptor to be described on human neutrophils, formyl peptide receptor 1 (FPR1), is one such receptor that plays a significant role in the execution of these functions through multiple intracellular signaling pathways. Recent work has highlighted important observations with regard to both receptor function and the importance and functional relevance of FPR1 in the pathogenesis of a range of both sterile and infective inflammatory conditions. In this review, we explore the multiple components of neutrophil migration and function in both health and disease, with a focus on the role of FPR1 in these processes. The current understanding of FPR1 structure, function, and signaling is examined, alongside discussion of the potential importance of FPR1 in inflammatory diseases suggesting that FPR1 is a key regulator of the inflammatory environment. PMID:25791526

  11. Avian host defense peptides.

    PubMed

    Cuperus, Tryntsje; Coorens, Maarten; van Dijk, Albert; Haagsman, Henk P

    2013-11-01

    Host defense peptides (HDPs) are important effector molecules of the innate immune system of vertebrates. These antimicrobial peptides are also present in invertebrates, plants and fungi. HDPs display broad-spectrum antimicrobial activities and fulfill an important role in the first line of defense of many organisms. It is becoming increasingly clear that in the animal kingdom the functions of HDPs are not confined to direct antimicrobial actions. Research in mammals has indicated that HDPs have many immunomodulatory functions and are also involved in other physiological processes ranging from development to wound healing. During the past five years our knowledge about avian HDPs has increased considerably. This review addresses our current knowledge on the evolution, regulation and biological functions of HDPs of birds.

  12. Peptide mass fingerprinting.

    PubMed

    Thiede, Bernd; Höhenwarter, Wolfgang; Krah, Alexander; Mattow, Jens; Schmid, Monika; Schmidt, Frank; Jungblut, Peter R

    2005-03-01

    Peptide mass fingerprinting by MALDI-MS and sequencing by tandem mass spectrometry have evolved into the major methods for identification of proteins following separation by two-dimensional gel electrophoresis, SDS-PAGE or liquid chromatography. One main technological goal of proteome analyses beside high sensitivity and automation was the comprehensive analysis of proteins. Therefore, the protein species level with the essential information on co- and post-translational modifications must be achieved. The power of peptide mass fingerprinting for protein identification was described here, as exemplified by the identification of protein species with high molecular masses (spectrin alpha and beta), low molecular masses (elongation factor EF-TU fragments), splice variants (alpha A crystallin), aggregates with disulfide bridges (alkylhydroperoxide reductase), and phosphorylated proteins (heat shock protein 27). Helpful tools for these analyses were the use of the minimal protein identifier concept and the software program MS-Screener to remove mass peaks assignable to contaminants and neighbor spots.

  13. Progressive inflammatory pathology in the retina of aluminum-fed 5xFAD transgenic mice.

    PubMed

    Pogue, A I; Dua, P; Hill, J M; Lukiw, W J

    2015-11-01

    At least 57 murine transgenic models for Alzheimer's disease (Tg-AD) have been developed to overexpress the 42 amino acid amyloid-beta (Aβ42) peptide in the central nervous system (CNS). These 'humanized murine Tg-AD models' have greatly expanded our understanding of the contribution of Aβ42 peptide-mediated pro-inflammatory neuropathology to the AD process. A number of independent laboratories using different amyloid-overexpressing Tg-AD models have shown that supplementation of murine Tg-AD diets and/or drinking water with aluminum significantly enhances Aβ42 peptide-mediated inflammatory pathology and AD-type cognitive change compared to animals receiving control diets. In humans AD-type pathology appears to originate in the limbic system and progressively spreads into primary processing and sensory regions such as the retina. In these studies, for the first time, we assess the propagation of Aβ42 and inflammatory signals into the retina of 5xFAD Tg-AD amyloid-overexpressing mice whose diets were supplemented with aluminum. The two most interesting findings were (1) that similar to other Tg-AD models, there was a significantly accelerated development of Aβ42 and inflammatory pathology in 5xFAD Tg-AD mice fed aluminum; and (2) in aluminum-supplemented animals, markers for inflammatory pathology appeared in both the brain and the retina as evidenced by an evolving presence of Aβ42 peptides, and accompanied by inflammatory markers - cyclooxygenase-2 (COX-2) and C-reactive protein (CRP). The results indicate that in the 5xFAD Tg-AD model aluminum not only enhances an Aβ42-mediated inflammatory degeneration of the brain but also appears to induce AD-type pathology in an anatomically-linked primary sensory area that involves vision. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Modulation in Natriuretic Peptides System in Experimental Colitis in Rats.

    PubMed

    Lee, Chang Ho; Ha, Gi Won; Kim, Jong Hun; Kim, Suhn Hee

    2016-04-01

    Renin-angiotensin system is involved in the pathophysiology of colonic inflammation. However, there are a few reports about modulation of natriuretic peptide system. This study investigates whether a local atrial natriuretic peptide (ANP) system exists in rat colon and whether ANP plays a role in the regulation of colonic motility in experimental colitis rat model. Experimental colitis was induced by an intake of 5 % dextran sulfate sodium (DSS) dissolved in tap water for 7 days. After rats were killed, plasma hormone concentrations and mRNAs for natriuretic peptide system were measured. Functional analysis of colonic motility in response to ANP was performed using taenia coli. DSS-treated colon showed an increased necrosis with massive infiltration of inflammatory cells. The colonic natriuretic peptide receptor-A mRNA level and particulate guanylyl cyclase activity in response to ANP from colonic tissue membranes were higher, and the mRNA levels of ANP and natriuretic peptide receptor-B were lower in DSS-treated rats than in control rats. ANP decreased the frequency of basal motility in a dose-dependent manner but did not change the amplitude. The inhibitory responses of frequency of basal motility to ANP and 8-bromo-cGMP were enhanced in DSS-treated rat colon. In conclusion, augmentation of inhibitory effect on basal motility by ANP in experimental colitis may be due an increased expression of colonic natriuretic peptide receptor-A mRNA. These data suggest that local natriuretic peptide system is partly involved in the pathophysiology of experimental colitis.

  15. Inflammatory mediators in epilepsy.

    PubMed

    Lorigados Pedre, Lourdes; Morales Chacón, Lilia M; Orozco Suárez, Sandra; Pavón Fuentes, Nancy; Estupiñán Díaz, Bárbara; Serrano Sánchez, Teresa; García Maeso, Iván; Rocha Arrieta, Luisa

    2013-01-01

    All common contributing factors to epilepsy such as trauma, malignancies and infections are accompanied by different levels of central nervous system inflammation that in turn have been associated with the occurrence of seizure. Emerging data from human brain tissue and experimental models of epilepsy support the proposed involvement of inflammation in epilepsy. Key mediators of this process include, among others: interleukin (IL) -1β, IL-6, tumor necrosis factor-α, adhesion molecules and component of complement. Recent advances suggest the involvement of specific inflammatory pathways in the pathogenesis of seizures in patients with pharmacoresistant temporal lobe epilepsy, highlighting the potential for new therapeutic strategies. This review provides an overview of the current knowledge on the relationship between inflammatory mediators and epilepsy. We also describe experimental and clinical evidence of inflammation in epilepsy with special emphasis on clinical aspects once the epileptogenic focus has been resected. Further insight into the complex role of inflammation in epileptogenesis may provide new treatment options.

  16. Chronic Inflammatory Demyelinating Polyneuropathy

    PubMed Central

    Dimachkie, Mazen M.; Barohn, Richard J.

    2014-01-01

    Opinion statement Chronic Inflammatory polyneuropathies are an important group of neuromuscular disorders that present chronically and progress over more than 8 weeks, being referred to as chronic inflammatory demyelinating polyneuropathy (CIDP). Despite tremendous progress in elucidating disease pathogenesis, the exact triggering event remains unknown. Our knowledge regarding diagnosis and management of CIDP and its variants continues to expand, resulting in improved opportunities for identification and treatment. Most clinical neurologists will be involved in the management of patients with these disorders, and should be familiar with available therapies for CIDP. We review the distinctive clinical, laboratory, and electro-diagnostic features that aid in diagnosis. We emphasize the importance of clinical patterns that define treatment responsiveness and the most appropriate therapies in order to improve prognosis. PMID:23564314

  17. Keratoconus: an inflammatory disorder?

    PubMed Central

    Galvis, V; Sherwin, T; Tello, A; Merayo, J; Barrera, R; Acera, A

    2015-01-01

    Keratoconus has been classically defined as a progressive, non-inflammatory condition, which produces a thinning and steepening of the cornea. Its pathophysiological mechanisms have been investigated for a long time. Both genetic and environmental factors have been associated with the disease. Recent studies have shown a significant role of proteolytic enzymes, cytokines, and free radicals; therefore, although keratoconus does not meet all the classic criteria for an inflammatory disease, the lack of inflammation has been questioned. The majority of studies in the tears of patients with keratoconus have found increased levels of interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α), and matrix metalloproteinase (MMP)-9. Eye rubbing, a proven risk factor for keratoconus, has been also shown recently to increase the tear levels of MMP-13, IL-6, and TNF-α. In the tear fluid of patients with ocular rosacea, IL-1α and MMP-9 have been reported to be significantly elevated, and cases of inferior corneal thinning, resembling keratoconus, have been reported. We performed a literature review of published biochemical changes in keratoconus that would support that this could be, at least in part, an inflammatory condition. PMID:25931166

  18. Keratoconus: an inflammatory disorder?

    PubMed

    Galvis, V; Sherwin, T; Tello, A; Merayo, J; Barrera, R; Acera, A

    2015-07-01

    Keratoconus has been classically defined as a progressive, non-inflammatory condition, which produces a thinning and steepening of the cornea. Its pathophysiological mechanisms have been investigated for a long time. Both genetic and environmental factors have been associated with the disease. Recent studies have shown a significant role of proteolytic enzymes, cytokines, and free radicals; therefore, although keratoconus does not meet all the classic criteria for an inflammatory disease, the lack of inflammation has been questioned. The majority of studies in the tears of patients with keratoconus have found increased levels of interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α), and matrix metalloproteinase (MMP)-9. Eye rubbing, a proven risk factor for keratoconus, has been also shown recently to increase the tear levels of MMP-13, IL-6, and TNF-α. In the tear fluid of patients with ocular rosacea, IL-1α and MMP-9 have been reported to be significantly elevated, and cases of inferior corneal thinning, resembling keratoconus, have been reported. We performed a literature review of published biochemical changes in keratoconus that would support that this could be, at least in part, an inflammatory condition.

  19. Pelvic inflammatory disease

    PubMed Central

    2008-01-01

    Introduction Pelvic inflammatory disease is caused by infection of the upper female genital tract and is often asymptomatic. Pelvic inflammatory disease is the most common gynaecological reason for admission to hospital in the USA and is diagnosed in almost 2% of women aged 16 to 45 years consulting their GP in England and Wales. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of empirical treatment compared with treatment delayed until the results of microbiological investigations are known? How do different antimicrobial regimens compare? What are the effects of routine antibiotic prophylaxis to prevent pelvic inflammatory disease before intrauterine contraceptive device (IUD) insertion? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found nine systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review, we present information relating to the effectiveness and safety of the following interventions: antibiotics (oral, parenteral, empirical treatment, treatment guided by test results, different durations, outpatient, inpatient), and routine antibiotic prophylaxis (before intrauterine device insertion in women at high risk or low risk). PMID:19450319

  20. [Inflammatory abdominal aortic aneurysm].

    PubMed

    Ziaja, K; Sedlak, L; Urbanek, T; Kostyra, J; Ludyga, T

    2000-01-01

    The reported incidence of inflammatory abdominal aortic aneurysm (IAAA) is from 2% to 14% of patients with abdominal aortic aneurysm and the etiology of this disease is still discussed--according to the literature several pathogenic theories have been proposed. From 1992 to 1997 32 patients with IAAA were operated on. The patients were mostly symptomatic--abdominal pain was present in 68.75% cases, back pain in 31.25%, fever in 12.5% and weight loss in 6.25% of the operated patients. In all the patients ultrasound examination was performed, in 4 patients CT and in 3 cases urography. All the patients were operated on and characteristic signs of inflammatory abdominal aortic aneurysm like: thickened aortic wall, perianeurysmal infiltration or retroperitoneal fibrosis with involvement of retroperitoneal structures were found. In all cases surgery was performed using transperitoneal approach; in three cases intraoperatively contiguous abdominal organs were injured, which was connected with their involvement into periaortic inflammation. In 4 cases clamping of the aorta was done at the level of the diaphragmatic hiatus. 3 patients (9.37%) died (one patient with ruptured abdominal aortic aneurysm). Authors present diagnostic procedures and the differences in the surgical tactic, emphasizing the necessity of the surgical therapy in patients with inflammatory abdominal aortic aneurysm.

  1. Inflammatory Cardiomyopathic Syndromes.

    PubMed

    Trachtenberg, Barry H; Hare, Joshua M

    2017-09-15

    Inflammatory activation occurs in nearly all forms of myocardial injury. In contrast, inflammatory cardiomyopathies refer to a diverse group of disorders in which inflammation of the heart (or myocarditis) is the proximate cause of myocardial dysfunction, causing injury that can range from a fully recoverable syndrome to one that leads to chronic remodeling and dilated cardiomyopathy. The most common cause of inflammatory cardiomyopathies in developed countries is lymphocytic myocarditis most commonly caused by a viral pathogenesis. In Latin America, cardiomyopathy caused by Chagas disease is endemic. The true incidence of myocarditis is unknown to the limited utilization and the poor sensitivity of endomyocardial biopsies (especially for patchy diseases such as lymphocytic myocarditis and sarcoidosis) using the gold-standard Dallas criteria. Emerging immunohistochemistry criteria and molecular diagnostic techniques are being developed that will improve diagnostic yield, provide additional clues into the pathophysiology, and offer an application of precision medicine to these important syndromes. Immunosuppression is recommended for patients with cardiac sarcoidosis, giant cell myocarditis, and myocarditis associated with connective tissue disorders and may be beneficial in chronic viral myocarditis once virus is cleared. Further trials of immunosuppression, antiviral, and immunomodulating therapies are needed. Together, with new molecular-based diagnostics and therapies tailored to specific pathogeneses, the outcome of patients with these disorders may improve. © 2017 American Heart Association, Inc.

  2. Pelvic inflammatory disease.

    PubMed

    Gradison, Margaret

    2012-04-15

    Pelvic inflammatory disease is a polymicrobial infection of the upper genital tract. It primarily affects young, sexually active women. The diagnosis is made clinically; no single test or study is sensitive or specific enough for a definitive diagnosis. Pelvic inflammatory disease should be suspected in at-risk patients who present with pelvic or lower abdominal pain with no identified etiology, and who have cervical motion, uterine, or adnexal tenderness. Chlamydia trachomatis and Neisseria gonorrhoeae are the most commonly implicated microorganisms; however, other microorganisms may be involved. The spectrum of disease ranges from asymptomatic to life-threatening tubo-ovarian abscess. Patients should be treated empirically, even if they present with few symptoms. Most women can be treated successfully as outpatients with a single dose of a parenteral cephalosporin plus oral doxycycline, with or without oral metronidazole. Delay in treatment may lead to major sequelae, including chronic pelvic pain, ectopic pregnancy, and infertility. Hospitalization and parenteral treatment are recommended if the patient is pregnant, has human immunodeficiency virus infection, does not respond to oral medication, or is severely ill. Strategies for preventing pelvic inflammatory disease include routine screening for chlamydia and patient education.

  3. C-peptide promotes lesion development in a mouse model of arteriosclerosis.

    PubMed

    Vasic, Dusica; Marx, Nikolaus; Sukhova, Galina; Bach, Helga; Durst, Renate; Grüb, Miriam; Hausauer, Angelina; Hombach, Vinzenz; Rottbauer, Wolfgang; Walcher, Daniel

    2012-04-01

    Patients with insulin resistance and early type 2 diabetes exhibit an increased propensity to develop a diffuse and extensive pattern of arteriosclerosis. Typically, these patients show elevated serum levels of the proinsulin cleavage product C-peptide and immunohistochemical data from our group revealed C-peptide deposition in early lesions of these individuals. Moreover, in vitro studies suggest that C-peptide could promote atherogenesis. This study examined whether C-peptide promotes vascular inflammation and lesion development in a mouse model of arteriosclerosis. ApoE-deficient mice on a high fat diet were treated with C-peptide or control injections for 12 weeks and the effect on lesion size and plaque composition was analysed. C-peptide treatment significantly increased C-peptide blood levels by 4.8-fold without having an effect on glucose or insulin levels, nor on the lipid profile. In these mice, C-peptide deposition in atherosclerotic plaques was significantly increased compared with controls. Moreover, lesions of C-peptide-treated mice contained significantly more macrophages (1.6 ± 0.3% versus 0.7 ± 0.2% positive area; P < 0.01) and more vascular smooth muscle cells (4.8 ± 0.6% versus 2.4 ± 0.3% positive area; P < 0.01). Finally, lipid deposition measured by Oil-red-O staining in the aortic arch was significantly higher in the C-peptide group compared with controls. Our results demonstrate that elevated C-peptide levels promote inflammatory cell infiltration and lesion development in ApoE-deficient mice without having metabolic effects. These data obtained in a mouse model of arteriosclerosis support the hypothesis that C-peptide may have an active role in atherogenesis in patients with diabetes and insulin resistance.

  4. Tryptophan end-tagging for promoted lipopolysaccharide interactions and anti-inflammatory effects.

    PubMed

    Singh, Shalini; Datta, Aritreyee; Schmidtchen, Artur; Bhunia, Anirban; Malmsten, Martin

    2017-03-16

    The objective of the present study is the investigation of possibilities for boosting peptide anti-inflammatory effects by tryptophan end-tagging, including identification of underlying mechanisms for this. In doing so, effects of tryptophan end-tagging of KYE21 (KYEITTIHNLFRKLTHRLFRR), a peptide derived from heparin co-factor II, on membrane and lipopolysaccharide (LPS) interactions were investigated by ellipsometry, NMR, fluorescence spectroscopy, and circular dichroism measurements. Through its N-terminal W stretch, WWWKYE21 displays higher membrane binding, liposome rupture, and bacterial killing than unmodified KYE21. Analogously, W-tagging promotes binding to E. coli LPS and to its endotoxic lipid A moiety. Furthermore, WWWKYE21 causes more stable peptide/LPS complexes than KYE21, as evidenced by detailed NMR studies, adopting a pronounced helical conformation, with a large hydrophobic surface at the N-terminus due to the presence of W-residues, and a flexible C-terminus due to presence of several positively charged arginine residues. Mirroring its increased affinity for LPS and lipid A, WWWKYE21 displays strongly increased anti-inflammatory effect due to a combination of direct lipid A binding, peptide-induced charge reversal of cell membranes for LPS scavenging, and peptide-induced fragmentation of LPS aggregates for improved phagocytosis. Importantly, potent anti-inflammatory effects were observed at low cell toxicity, demonstrated for both monocytes and erythrocytes.

  5. Innate immune dysfunction in inflammatory bowel disease.

    PubMed

    Gersemann, M; Wehkamp, J; Stange, E F

    2012-05-01

    The pathogenetic mechanisms that cause the two types of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are still under investigation. Nevertheless, there is broad agreement that luminal microbes are of particular relevance in the development of these conditions. In recent years, increasing evidence has shown that defects in the innate immunity are at the centre of both types of IBD. The innate intestinal barrier is provided by the epithelium which secretes antimicrobial peptides (so-called defensins) that are retained in the mucus layer. In ileal CD, the alpha-defensins are lacking owing to several Paneth cell defects. In colonic CD, the expression of beta-defensins is inadequate. This may be related to downregulation of the transcription factor peroxisome proliferator-activated receptor-gamma and in some cohorts is associated with a reduced HBD2 gene copy number. In UC, the mucus layer, which protects the host from the enormous amounts of luminal microbes, is defective. This is accompanied by an insufficient differentiation from intestinal stem cells towards goblet cells. All these disturbances in the gut barrier shift the balance from epithelial defence towards bacterial offence. The current treatment for CD and UC is based on suppression of this secondary inflammatory process. In future, patients may benefit from new therapeutic approaches stimulating the protective innate immune system.

  6. [Hydrolysis of peptides by immobilized bacterial peptide hydrolases].

    PubMed

    Nekliudov, A D; Deniakina, E K

    2004-01-01

    The feasibility of hydrolysis of a mixture of peptides with an enzyme from the bacterium Xanthomonas rubrilineans, displaying a peptidase activity and immobilized on aluminum oxide, was studied. Kinetic schemes and equations allowing for approaching quantitative description of peptide hydrolysis in complex mixtures containing free amino acids and peptides were obtained. It was demonstrated that as a result of hydrolysis, the content of free amino acids in hydrolysates decreased 2.5- to 3-fold and the molecular weight of the constituent peptides, 2-fold.

  7. Inflammatory dilated cardiomyopathy (DCMI).

    PubMed

    Maisch, Bernhard; Richter, Anette; Sandmöller, Andrea; Portig, Irene; Pankuweit, Sabine

    2005-09-01

    Cardiomyopathies are heart muscle diseases, which have been defined by their central hemodynamics and macropathology and divided in five major forms: dilated (DCM), hypertrophic (HCM), restrictive (RCM), right ventricular (RVCM), and nonclassifiable cardiomyopathies (NCCM). Furthermore, the most recent WHO/WHF definition also comprises, among the specific cardiomyopathies, inflammatory cardiomyopathy as a distinct entity, defined as myocarditis in association with cardiac dysfunction. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy were recognized. Viral cardiomyopathy has been defined as viral persistence in a dilated heart. It may be accompanied by myocardial inflammation and then termed inflammatory viral cardiomyopathy (or viral myocarditis with cardiomegaly). If no inflammation is observed in the biopsy of a dilated heart (< 14 lymphocytes and macrophages/mm(2)), the term viral cardiomyopathy or viral persistence in DCM should be applied according to the WHF Task Force recommendations. Within the German heart failure net it is the authors' working hypothesis, that DCM shares genetic risk factors with other diseases of presumed autoimmune etiology and, therefore, the same multiple genes in combination with environmental factors lead to numerous different autoimmune diseases including DCM. Therefore, the authors' primary goal is to acquire epidemiologic data of patients with DCM regarding an infectious and inflammatory etiology of the disease. Circumstantial evidence points to a major role of viral myocarditis in the etiology of DCM. The common presence of viral genetic material in the myocardium of patients with DCM provides the most compelling evidence, but proof of causality is still lacking. In addition, autoimmune reactions have been described in many studies, indicating them as an important etiologic factor. Nevertheless, data on the proportion of patients, in whom both mechanisms play a role are still missing.A pivotal role for

  8. Regulation of Airway Inflammation by G-protein Regulatory Motif Peptides of AGS3 protein

    PubMed Central

    Choi, IL-Whan; Ahn, Do Whan; Choi, Jang-Kyu; Cha, Hee-Jae; Ock, Mee Sun; You, EunAe; Rhee, SangMyung; Kim, Kwang Chul; Choi, Yung Hyun; Song, Kyoung Seob

    2016-01-01

    Respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and lung infections have critical consequences on mortality and morbidity in humans. The aims of the present study were to examine the mechanisms by which CXCL12 affects MUC1 transcription and airway inflammation, which depend on activator of G-protein signaling (AGS) 3 and to identify specific molecules that suppress CXCL12-induced airway inflammation by acting on G-protein-coupled receptors. Herein, AGS3 suppresses CXCL12-mediated upregulation of MUC1 and TNFα by regulating Gαi. We found that the G-protein regulatory (GPR) motif peptide in AGS3 binds to Gαi and downregulates MUC1 expression; in contrast, this motif upregulates TNFα expression. Mutated GPR Q34A peptide increased the expression of MUC1 and TGFβ but decreased the expression of TNFα and IL-6. Moreover, CXCR4-induced dendritic extensions in 2D and 3D matrix cultures were inhibited by the GPR Q34A peptide compared with a wild-type GPR peptide. The GPR Q34A peptide also inhibited CXCL12-induced morphological changes and inflammatory cell infiltration in the mouse lung, and production of inflammatory cytokines in bronchoalveolar lavage (BAL) fluid and the lungs. Our data indicate that the GPR motif of AGS3 is critical for regulating MUC1/Muc1 expression and cytokine production in the inflammatory microenvironment. PMID:27270970

  9. Uncoupling Angiogenesis and Inflammation in Peripheral Artery Disease with Therapeutic Peptide-loaded Microgels

    PubMed Central

    Zachman, Angela L.; Wang, Xintong; Tucker-Schwartz, Jason M.; Fitzpatrick, Sean T.; Lee, Sue H.; Guelcher, Scott A.; Skala, Melissa C.; Sung, Hak-Joon

    2014-01-01

    Peripheral artery disease (PAD) is characterized by vessel occlusion and ischemia in the limbs. Treatment for PAD with surgical interventions has been showing limited success. Moreover, recent clinical trials with treatment of angiogenic growth factors proved ineffective as increased angiogenesis triggered severe inflammation in a proportionally coupled fashion. Hence, the overarching goal of this research was to address this issue by developing a biomaterial system that enables controlled, dual delivery of pro-angiogenic C16 and anti-inflammatory Ac-SDKP peptides in a minimally-invasive way. To achieve the goal, a peptide-loaded injectable microgel system was developed and tested in a mouse model of PAD. When delivered through multiple, low volume injections, the combination of C16 and Ac-SDKP peptides promoted angiogenesis, muscle regeneration, and perfusion recovery, while minimizing detrimental inflammation. Additionally, this peptide combination regulated inflammatory TNF-α pathways independently of MMP-9 mediated pathways of angiogenesis in vitro, suggesting a potential mechanism by which angiogenic and inflammatory responses can be uncoupled in the context of PAD. This study demonstrates a translatable potential of the dual peptide-loaded injectable microgel system for PAD treatment. PMID:25154665

  10. Inflammatory signaling in human Tuberculosis granulomas is spatially organized

    PubMed Central

    Marakalala, Mohlopheni J.; Raju, Ravikiran M.; Sharma, Kirti; Zhang, Yanjia J.; Eugenin, Eliseo A.; Prideaux, Brendan; Daudelin, Isaac B.; Chen, Pei-Yu; Booty, Matthew G.; Kim, Jin Hee; Eum, Seok Yong; Via, Laura E.; Behar, Samuel M.; Barry, Clifton E.; Mann, Matthias; Dartois, Véronique; Rubin, Eric J.

    2016-01-01

    Granulomas are the pathological hallmark of tuberculosis (TB). However, their function and mechanisms of formation remain poorly understood. To understand the role of granulomas in TB, we analyzed the proteomes of granulomas from subjects with tuberculosis in an unbiased fashion. Using laser capture microdissection, mass spectrometry and confocal microscopy, we generated detailed molecular maps of human granulomas. We found that the centers of granulomas possess a pro-inflammatory environment characterized by anti-microbial peptides, ROS and pro-inflammatory eicosanoids. Conversely, the tissue surrounding the caseum possesses a comparatively anti-inflammatory signature. These findings are consistent across a set of six subjects and in rabbits. While the balance between systemic pro- and anti-inflammatory signals is crucial to TB disease outcome, here we find that these signals are physically segregated within each granuloma. The protein and lipid snapshots of human and rabbit lesions analysed here suggest that the pathologic response to TB is shaped by the precise anatomical localization of these inflammatory pathways during the development of the granuloma. PMID:27043495

  11. Vitamin D and inflammatory diseases

    PubMed Central

    Yin, Kai; Agrawal, Devendra K

    2014-01-01

    Beyond its critical function in calcium homeostasis, vitamin D has recently been found to play an important role in the modulation of the immune/inflammation system via regulating the production of inflammatory cytokines and inhibiting the proliferation of proinflammatory cells, both of which are crucial for the pathogenesis of inflammatory diseases. Several studies have associated lower vitamin D status with increased risk and unfavorable outcome of acute infections. Vitamin D supplementation bolsters clinical responses to acute infection. Moreover, chronic inflammatory diseases, such as atherosclerosis-related cardiovascular disease, asthma, inflammatory bowel disease, chronic kidney disease, nonalcoholic fatty liver disease, and others, tend to have lower vitamin D status, which may play a pleiotropic role in the pathogenesis of the diseases. In this article, we review recent epidemiological and interventional studies of vitamin D in various inflammatory diseases. The potential mechanisms of vitamin D in regulating immune/inflammatory responses in inflammatory diseases are also discussed. PMID:24971027

  12. Macrocyclization of Unprotected Peptide Isocyanates.

    PubMed

    Vinogradov, Alexander A; Choo, Zi-Ning; Totaro, Kyle A; Pentelute, Bradley L

    2016-03-18

    A chemistry for the facile two-component macrocyclization of unprotected peptide isocyanates is described. Starting from peptides containing two glutamic acid γ-hydrazide residues, isocyanates can be readily accessed and cyclized with hydrazides of dicarboxylic acids. The choice of a nucleophilic linker allows for the facile modulation of biochemical properties of a macrocyclic peptide. Four cyclic NYAD-1 analogues were synthesized using the described method and displayed a range of biological activities.

  13. The Synthetic Antimicrobial Peptide 19-2.5 Interacts with Heparanase and Heparan Sulfate in Murine and Human Sepsis

    PubMed Central

    Martin, Lukas; De Santis, Rebecca; Koczera, Patrick; Simons, Nadine; Haase, Hajo; Heinbockel, Lena; Brandenburg, Klaus; Marx, Gernot; Schuerholz, Tobias

    2015-01-01

    Heparanase is an endo-β-glucuronidase that cleaves heparan sulfate side chains from their proteoglycans. Thereby, heparanase liberates highly potent circulating heparan sulfate-fragments (HS-fragments) and triggers the fatal and excessive inflammatory response in sepsis. As a potential anti-inflammatory agent for sepsis therapy, peptide 19–2.5 belongs to the class of synthetic anti-lipopolysaccharide peptides; however, its activity is not restricted to Gram-negative bacterial infection. We hypothesized that peptide 19–2.5 interacts with heparanase and/or HS, thereby reducing the levels of circulating HS-fragments in murine and human sepsis. Our data indicate that the treatment of septic mice with peptide 19–2.5 compared to untreated control animals lowers levels of plasma heparanase and circulating HS-fragments and reduces heparanase activity. Additionally, mRNA levels of heparanase in heart, liver, lung, kidney and spleen are downregulated in septic mice treated with peptide 19–2.5 compared to untreated control animals. In humans, plasma heparanase level and activity are elevated in septic shock. The ex vivo addition of peptide 19–2.5 to plasma of septic shock patients decreases heparanase activity but not heparanase level. Isothermal titration calorimetry revealed a strong exothermic reaction between peptide 19–2.5 and heparanase and HS-fragments. However, a saturation character has been identified only in the peptide 19–2.5 and HS interaction. In conclusion, the findings of our current study indicate that peptide 19–2.5 interacts with heparanase, which is elevated in murine and human sepsis and consecutively attenuates the generation of circulating HS-fragments in systemic inflammation. Thus, peptide 19–2.5 seems to be a potential anti-inflammatory agent in sepsis. PMID:26600070

  14. Antitumor Peptides from Marine Organisms

    PubMed Central

    Zheng, Lan-Hong; Wang, Yue-Jun; Sheng, Jun; Wang, Fang; Zheng, Yuan; Lin, Xiu-Kun; Sun, Mi

    2011-01-01

    The biodiversity of the marine environment and the associated chemical diversity constitute a practically unlimited resource of new antitumor agents in the field of the development of marine bioactive substances. In this review, the progress on studies of antitumor peptides from marine sources is provided. The biological properties and mechanisms of action of different marine peptides are described; information about their molecular diversity is also presented. Novel peptides that induce apoptosis signal pathway, affect the tubulin-microtubule equilibrium and inhibit angiogenesis are presented in association with their pharmacological properties. It is intended to provide useful information for further research in the fields of marine antitumor peptides. PMID:22072999

  15. Improving Peptide Applications Using Nanotechnology.

    PubMed

    Narayanaswamy, Radhika; Wang, Tao; Torchilin, Vladimir P

    2016-01-01

    Peptides are being successfully used in various fields including therapy and drug delivery. With advancement in nanotechnology and targeted delivery carrier systems, suitable modification of peptides has enabled achievement of many desirable goals over-riding some of the major disadvantages associated with the delivery of peptides in vivo. Conjugation or physical encapsulation of peptides to various nanocarriers, such as liposomes, micelles and solid-lipid nanoparticles, has improved their in vivo performance multi-fold. The amenability of peptides to modification in chemistry and functionalization with suitable nanocarriers are very relevant aspects in their use and have led to the use of 'smart' nanoparticles with suitable linker chemistries that favor peptide targeting or release at the desired sites, minimizing off-target effects. This review focuses on how nanotechnology has been used to improve the number of peptide applications. The paper also focuses on the chemistry behind peptide conjugation to nanocarriers, the commonly employed linker chemistries and the several improvements that have already been achieved in the areas of peptide use with the help of nanotechnology.

  16. Peptides that influence membrane topology

    NASA Astrophysics Data System (ADS)

    Wong, Gerard C. L.

    2014-03-01

    We examine the mechanism of a range of polypeptides that influence membrane topology, including antimicrobial peptides, cell penetrating peptides, viral fusion peptides, and apoptosis proteins, and show how a combination of geometry, coordination chemistry, and soft matter physics can be used to approach a unified understanding. We will also show how such peptides can impact biomedical problems such as auto-immune diseases (psoriasis, lupus), infectious diseases (viral and bacterial infections), and mitochondrial pathologies (under-regulated apoptosis leads to neurodegenerative diseases whereas over-regulated apoptosis leads to cancer.)

  17. The PeptideAtlas Project.

    PubMed

    Deutsch, Eric W

    2010-01-01

    PeptideAtlas is a multi-species compendium of peptides observed with tandem mass spectrometry methods. Raw mass spectrometer output files are collected from the community and reprocessed through a uniform analysis and validation pipeline that continues to advance. The results are loaded into a database and the information derived from the raw data is returned to the community via several web-based data exploration tools. The PeptideAtlas resource is useful for experiment planning, improving genome annotation, and other data mining projects. PeptideAtlas has become especially useful for planning targeted proteomics experiments.

  18. Antitumor peptides from marine organisms.

    PubMed

    Zheng, Lan-Hong; Wang, Yue-Jun; Sheng, Jun; Wang, Fang; Zheng, Yuan; Lin, Xiu-Kun; Sun, Mi

    2011-01-01

    The biodiversity of the marine environment and the associated chemical diversity constitute a practically unlimited resource of new antitumor agents in the field of the development of marine bioactive substances. In this review, the progress on studies of antitumor peptides from marine sources is provided. The biological properties and mechanisms of action of different marine peptides are described; information about their molecular diversity is also presented. Novel peptides that induce apoptosis signal pathway, affect the tubulin-microtubule equilibrium and inhibit angiogenesis are presented in association with their pharmacological properties. It is intended to provide useful information for further research in the fields of marine antitumor peptides.

  19. Biodiscovery of aluminum binding peptides

    NASA Astrophysics Data System (ADS)

    Adams, Bryn L.; Sarkes, Deborah A.; Finch, Amethist S.; Hurley, Margaret M.; Stratis-Cullum, Dimitra

    2013-05-01

    Cell surface peptide display systems are large and diverse libraries of peptides (7-15 amino acids) which are presented by a display scaffold hosted by a phage (virus), bacteria, or yeast cell. This allows the selfsustaining peptide libraries to be rapidly screened for high affinity binders to a given target of interest, and those binders quickly identified. Peptide display systems have traditionally been utilized in conjunction with organic-based targets, such as protein toxins or carbon nanotubes. However, this technology has been expanded for use with inorganic targets, such as metals, for biofabrication, hybrid material assembly and corrosion prevention. While most current peptide display systems employ viruses to host the display scaffold, we have recently shown that a bacterial host, Escherichia coli, displaying peptides in the ubiquitous, membrane protein scaffold eCPX can also provide specific peptide binders to an organic target. We have, for the first time, extended the use of this bacterial peptide display system for the biodiscovery of aluminum binding 15mer peptides. We will present the process of biopanning with macroscopic inorganic targets, binder enrichment, and binder isolation and discovery.

  20. Oral inflammation, a role for antimicrobial peptide modulation of cytokine and chemokine responses.

    PubMed

    Brogden, Kim A; Johnson, Georgia K; Vincent, Steven D; Abbasi, Taher; Vali, Shireen

    2013-10-01

    Acute and chronic inflammation commonly occurs throughout the oral cavity. The most common causes are physical damage and microbial infections, and less frequently immune reactions and malignant changes. All of these processes result in the induction of antimicrobial peptides, chemokines and cytokines that lead to cellular infiltrates, a vascular response, tissue destruction and cellular proliferation. A fascinating concept developing in the current literature suggests that antimicrobial peptides modulate the production of chemokines, cytokines and other cellular mediators and that this may have a larger ramification as an underlying mechanism mediating inflammation. Here, we propose that the ability of antimicrobial peptides to induce chemokines and anti-inflammatory or proinflammatory cytokines plays an important role in the early events of oral inflammation and may be a target for the prevention or treatment of oral inflammatory conditions.

  1. Cell penetrating peptide inhibitors of Nuclear Factor-kappa B

    PubMed Central

    Orange, J. S.; May, M. J.

    2010-01-01

    The nuclear factor kappa B (NF-κB) transcription factors are activated by a range of stimuli including pro-inflammatory cytokines. Active NF-κB regulates the expression of genes involved in inflammation and cell survival and aberrant NF-κB activity plays pathological roles in certain types of cancer and diseases characterized by chronic inflammation. NF-κB signaling is an attractive target for the development of novel anti-inflammatory or anti-cancer drugs and we discuss here how the method of peptide transduction has been used to specifically target NF-κB. Peptide transduction relies on the ability of certain small cell-penetrating peptides (CPPs) to enter cells, and a panel of CPP-linked inhibitors (CPP-Is) has been developed to directly inhibit NF-κB signaling. Remarkably, several of these NF-κB-targeting CPP-Is are effective in vivo and therefore offer exciting potential in the clinical setting. PMID:18668204

  2. Chronic inflammatory systemic diseases

    PubMed Central

    Straub, Rainer H.; Schradin, Carsten

    2016-01-01

    It has been recognized that during chronic inflammatory systemic diseases (CIDs) maladaptations of the immune, nervous, endocrine and reproductive system occur. Maladaptation leads to disease sequelae in CIDs. The ultimate reason of disease sequelae in CIDs remained unclear because clinicians do not consider bodily energy trade-offs and evolutionary medicine. We review the evolution of physiological supersystems, fitness consequences of genes involved in CIDs during different life-history stages, environmental factors of CIDs, energy trade-offs during inflammatory episodes and the non-specificity of CIDs. Incorporating bodily energy regulation into evolutionary medicine builds a framework to better understand pathophysiology of CIDs by considering that genes and networks used are positively selected if they serve acute, highly energy-consuming inflammation. It is predicted that genes that protect energy stores are positively selected (as immune memory). This could explain why energy-demanding inflammatory episodes like infectious diseases must be terminated within 3–8 weeks to be adaptive, and otherwise become maladaptive. Considering energy regulation as an evolved adaptive trait explains why many known sequelae of different CIDs must be uniform. These are, e.g. sickness behavior/fatigue/depressive symptoms, sleep disturbance, anorexia, malnutrition, muscle wasting—cachexia, cachectic obesity, insulin resistance with hyperinsulinemia, dyslipidemia, alterations of steroid hormone axes, disturbances of the hypothalamic-pituitary-gonadal (HPG) axis, hypertension, bone loss and hypercoagulability. Considering evolved energy trade-offs helps us to understand how an energy imbalance can lead to the disease sequelae of CIDs. In the future, clinicians must translate this knowledge into early diagnosis and symptomatic treatment in CIDs. PMID:26817483

  3. Inflammatory bowel disease unclassified

    PubMed Central

    Zhou, Ning; Chen, Wei-xing; Chen, Shao-hua; Xu, Cheng-fu; Li, You-ming

    2011-01-01

    Objective: Inflammatory bowel diseases (IBDs) are idiopathic, chronic, and inflammatory intestinal disorders. The two main types, ulcerative colitis (UC) and Crohn’s disease (CD), sometimes mimic each other and are not readily distinguishable. The purpose of this study was to present a series of hospitalized cases, which could not initially be classified as a subtype of IBD, and to try to note roles of the terms indeterminate colitis (IC) and inflammatory bowel disease unclassified (IBDU) when such a dilemma arises. Methods: Medical records of 477 patients hospitalized due to IBD, during the period of January 2002 to April 2009, were retrospectively studied in the present paper. All available previous biopsies from endoscopies of these patients were reanalyzed. Results: Twenty-seven of 477 IBD patients (5.7%) had been initially diagnosed as having IBDU. Of them, 23 received colonoscopy and histological examinations in our hospital. A total of 90% (9/10) and 66.7% (4/6) of patients, respectively, had a positive finding via wireless capsule endoscopy (CE) and double-balloon enteroscopy (DBE). The barium-swallow or small bowel follow-through (SBFT) was performed on 11 patients. Positive changes were observed under computer tomographic (CT) scanning in 89.5% (17/19) of patients. Reasonable treatment strategies were employed for all patients. Conclusions: Our data indicate that IBDU accounts for 5.7% of initial diagnoses of IBD. The definition of IBDU is valuable in clinical practice. For those who had no clear clinical, endoscopic, histological, or other features affording a diagnosis of either UC or CD, IBDU could be used parenthetically. PMID:21462383

  4. Targeting peripheral opioid receptors to promote analgesic and anti-inflammatory actions

    PubMed Central

    Iwaszkiewicz, Katerina S.; Schneider, Jennifer J.; Hua, Susan

    2013-01-01

    Mechanisms of endogenous pain control are significant. Increasing studies have clearly produced evidence for the clinical usefulness of opioids in peripheral analgesia. The immune system uses mechanisms of cell migration not only to fight pathogens but also to control pain and inflammation within injured tissue. It has been demonstrated that peripheral inflammatory pain can be effectively controlled by an interaction of immune cell-derived opioid peptides with opioid receptors on peripheral sensory nerve terminals. Experimental and clinical studies have clearly shown that activation of peripheral opioid receptors with exogenous opioid agonists and endogenous opioid peptides are able to produce significant analgesic and anti-inflammatory effects, without central opioid mediated side effects (e.g., respiratory depression, sedation, tolerance, dependence). This article will focus on the role of opioids in peripheral inflammatory conditions and the clinical implications of targeting peripheral opioid receptors. PMID:24167491

  5. Peptide Amyloid Surface Display

    PubMed Central

    2015-01-01

    Homomeric self-assembly of peptides into amyloid fibers is a feature of many diseases. A central role has been suggested for the lateral fiber surface affecting gains of toxic function. To investigate this, a protein scaffold that presents a discrete, parallel β-sheet surface for amyloid subdomains up to eight residues in length has been designed. Scaffolds that present the fiber surface of islet amyloid polypeptide (IAPP) were prepared. The designs show sequence-specific surface effects apparent in that they gain the capacity to attenuate rates of IAPP self-assembly in solution and affect IAPP-induced toxicity in insulin-secreting cells. PMID:25541905

  6. Peptides and food intake.

    PubMed

    Sobrino Crespo, Carmen; Perianes Cachero, Aránzazu; Puebla Jiménez, Lilian; Barrios, Vicente; Arilla Ferreiro, Eduardo

    2014-01-01

    The mechanisms for controlling food intake involve mainly an interplay between gut, brain, and adipose tissue (AT), among the major organs. Parasympathetic, sympathetic, and other systems are required for communication between the brain satiety center, gut, and AT. These neuronal circuits include a variety of peptides and hormones, being ghrelin the only orexigenic molecule known, whereas the plethora of other factors are inhibitors of appetite, suggesting its physiological relevance in the regulation of food intake and energy homeostasis. Nutrients generated by food digestion have been proposed to activate G-protein-coupled receptors on the luminal side of enteroendocrine cells, e.g., the L-cells. This stimulates the release of gut hormones into the circulation such as glucagon-like peptide-1 (GLP-1), oxyntomodulin, pancreatic polypeptides, peptide tyrosine tyrosine, and cholecystokinin, which inhibit appetite. Ghrelin is a peptide secreted from the stomach and, in contrast to other gut hormones, plasma levels decrease after a meal and potently stimulate food intake. Other circulating factors such as insulin and leptin relay information regarding long-term energy stores. Both hormones circulate at proportional levels to body fat content, enter the CNS proportionally to their plasma levels, and reduce food intake. Circulating hormones can influence the activity of the arcuate nucleus (ARC) neurons of the hypothalamus, after passing across the median eminence. Circulating factors such as gut hormones may also influence the nucleus of the tractus solitarius (NTS) through the adjacent circumventricular organ. On the other hand, gastrointestinal vagal afferents converge in the NTS of the brainstem. Neural projections from the NTS, in turn, carry signals to the hypothalamus. The ARC acts as an integrative center, with two major subpopulations of neurons influencing appetite, one of them coexpressing neuropeptide Y and agouti-related protein (AgRP) that increases food

  7. Plant antimicrobial peptides.

    PubMed

    Nawrot, Robert; Barylski, Jakub; Nowicki, Grzegorz; Broniarczyk, Justyna; Buchwald, Waldemar; Goździcka-Józefiak, Anna

    2014-05-01

    Plant antimicrobial peptides (AMPs) are a component of barrier defense system of plants. They have been isolated from roots, seeds, flowers, stems, and leaves of a wide variety of species and have activities towards phytopathogens, as well as against bacteria pathogenic to humans. Thus, plant AMPs are considered as promising antibiotic compounds with important biotechnological applications. Plant AMPs are grouped into several families and share general features such as positive charge, the presence of disulfide bonds (which stabilize the structure), and the mechanism of action targeting outer membrane structures.

  8. Peptides and Food Intake

    PubMed Central

    Sobrino Crespo, Carmen; Perianes Cachero, Aránzazu; Puebla Jiménez, Lilian; Barrios, Vicente; Arilla Ferreiro, Eduardo

    2014-01-01

    The mechanisms for controlling food intake involve mainly an interplay between gut, brain, and adipose tissue (AT), among the major organs. Parasympathetic, sympathetic, and other systems are required for communication between the brain satiety center, gut, and AT. These neuronal circuits include a variety of peptides and hormones, being ghrelin the only orexigenic molecule known, whereas the plethora of other factors are inhibitors of appetite, suggesting its physiological relevance in the regulation of food intake and energy homeostasis. Nutrients generated by food digestion have been proposed to activate G-protein-coupled receptors on the luminal side of enteroendocrine cells, e.g., the L-cells. This stimulates the release of gut hormones into the circulation such as glucagon-like peptide-1 (GLP-1), oxyntomodulin, pancreatic polypeptides, peptide tyrosine tyrosine, and cholecystokinin, which inhibit appetite. Ghrelin is a peptide secreted from the stomach and, in contrast to other gut hormones, plasma levels decrease after a meal and potently stimulate food intake. Other circulating factors such as insulin and leptin relay information regarding long-term energy stores. Both hormones circulate at proportional levels to body fat content, enter the CNS proportionally to their plasma levels, and reduce food intake. Circulating hormones can influence the activity of the arcuate nucleus (ARC) neurons of the hypothalamus, after passing across the median eminence. Circulating factors such as gut hormones may also influence the nucleus of the tractus solitarius (NTS) through the adjacent circumventricular organ. On the other hand, gastrointestinal vagal afferents converge in the NTS of the brainstem. Neural projections from the NTS, in turn, carry signals to the hypothalamus. The ARC acts as an integrative center, with two major subpopulations of neurons influencing appetite, one of them coexpressing neuropeptide Y and agouti-related protein (AgRP) that increases food

  9. Enhancement of the inhibitory effect of an IL-15 antagonist peptide by alanine scanning.

    PubMed

    Savio, Alicia Santos; Acosta, Osvaldo Reyes; Pérez, Haydee Gerónimo; Alvarez, Yunier Rodríguez; Chico, Araceli; Pérez, Hilda Garay; Ojeda, Miriam Ojeda; Aguero, Celia Aurora Arrieta; Estévez, Miguel; Nieto, Gerardo Guillen

    2012-01-01

    IL-15 is a proinflammatory cytokine that acts early in the inflammatory response and has been associated with several autoimmune diseases including rheumatoid arthritis, where it had been proposed as a therapeutic target. We recently reported an IL-15 antagonist peptide corresponding to sequence 36-45 of IL-15 (KVTAMKCFLL) named P8, which specifically binds to IL-15Rα and inhibits IL-15 biological activity with a half maximal inhibitory concentration (IC50) of 130 µ m in CTLL-2 proliferation assay. In order to improve binding of peptide P8 to the receptor IL-15Rα, we used an Ala scan strategy to study contribution of each individual amino acid to the peptide's antagonist effect. Here, we found that Phe and Cys are important for peptide binding to IL-15Rα. We also investigated other single site mutations and replaced the second Lys in the sequence by the polar non-charged amino acid threonine. The resulting peptide [K6T]P8 exhibited a higher activity than P8 with an IC50 of 24 µm. We also found that this peptide was more active than peptide P8 in the inhibition of TNFα secretion by synovial cells from rheumatoid arthritis patients. The peptide [K6T]P8 described in this work is a new type of IL-15 antagonist and constitutes a potential therapeutic agent for rheumatoid arthritis.

  10. Antifungal Activities of Peptides Derived from Domain 5 of High-Molecular-Weight Kininogen

    PubMed Central

    Sonesson, Andreas; Nordahl, Emma Andersson; Malmsten, Martin; Schmidtchen, Artur

    2011-01-01

    In both immunocompromised and immunocompetent patients, Candida and Malassezia are causing or triggering clinical manifestations such as cutaneous infections and atopic eczema. The innate immune system provides rapid responses to microbial invaders, without requiring prior stimulation, through a sophisticated system of antimicrobial peptides (AMPs). High molecular weight kininogen (HMWK) and components of the contact system have previously been reported to bind to Candida and other pathogens, leading to activation of the contact system. A cutaneous Candida infection is characterized by an accumulation of neutrophils, leading to an inflammatory response and release of enzymatically active substances. In the present study we demonstrate that antifungal peptide fragments are generated through proteolytic degradation of HMWK. The recombinant domain 5 (rD5) of HMWK, D5-derived peptides, as well as hydrophobically modified D5-derived peptides efficiently killed Candida and Malassezia. Furthermore, the antifungal activity of modified peptides was studied at physiological conditions. Binding of a D5-derived peptide, HKH20 (His479-His498), to the fungal cell membrane was visualized by fluorescence microscopy. Our data disclose a novel antifungal activity of D5-derived peptides and also show that proteolytic cleavage of HMWK results in fragments exerting antifungal activity. Of therapeutic interest is that structurally modified peptides show an enhanced antifungal activity. PMID:21941573

  11. Chronic inflammatory demyelinating polyneuropathy.

    PubMed

    Gorson, Kenneth C; Katz, Jonathan

    2013-05-01

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune disorder of the peripheral nervous system. This article highlights our current understanding of the condition along with its phenotypic variants that are encountered in clinical practice. The diagnostic evaluation of CIDP includes laboratory studies to detect associated medical conditions and electrodiagnostic studies to assess for demyelination. Current treatment options include corticosteroids, plasma exchange, and intravenous immune globulin, along with alternative therapies that may be used as corticosteroid-sparing agents or for treatment-refractory cases. Approximately 85% to 90% of patients eventually improve or stabilize with treatment, and the long-term prognosis of CIDP is favorable.

  12. Dual host-defence functions of SPLUNC2/PSP and synthetic peptides derived from the protein.

    PubMed

    Gorr, Sven-Ulrik; Abdolhosseini, Mahsa; Shelar, Anuradha; Sotsky, Julie

    2011-08-01

    PSP (parotid secretory protein)/SPLUNC2 (short palate, lung and nasal epithelium clone 2) is expressed in human salivary glands and saliva. The protein exists as an N-glycosylated and non-glycosylated form and both appear to induce agglutination of bacteria, a major antibacterial function for salivary proteins. Both forms of PSP/SPLUNC2 bind LPS (lipopolysaccharide), suggesting that the protein may also play an anti-inflammatory role. Based on the predicted structure of PSP/SPLUNC2 and the location of known antibacterial and anti-inflammatory peptides in BPI (bactericidal/permeability-increasing protein) and LBP (LPS-binding protein), we designed GL13NH2 and GL13K, synthetic peptides that capture these proposed functions of PSP/SPLUNC2. GL13NH3 agglutinates bacteria, leading to increased clearance by macrophages and reduced spread of infection in a plant model. GL13K kills bacteria with a minimal inhibitory concentration of 5-10 μg/ml, kills bacteria in biofilm and retains activity in 150 mM NaCl and 50% saliva. Both peptides block endotoxin action, but only GL13K appears to bind endotoxin. The peptides do not cause haemolysis, haemagglutination in serum, inhibit mammalian cell proliferation or induce an inflammatory response in macrophages. These results suggest that the GL13NH2 and the modified peptide GL13K capture the biological activity of PSP/SPLUNC2 and can serve as lead compounds for the development of novel antimicrobial and anti-inflammatory peptides.

  13. Anti-inflammatory effects of phytochemicals from fruits, vegetables, and food legumes: A review.

    PubMed

    Zhu, Fengmei; Du, Bin; Xu, Baojun

    2017-06-12

    Inflammation is the first biological response of the immune system to infection, injury or irritation. Evidence suggests that the anti-inflammatory effect is mediated through the regulation of various inflammatory cytokines, such as nitric oxide, interleukins, tumor necrosis factor alpha-α, interferon gamma-γ as well as noncytokine mediator, prostaglandin E2. Fruits, vegetables, and food legumes contain high levels of phytochemicals that show anti-inflammatory effect, but their mechanisms of actions have not been completely identified. The aim of this paper was to summarize the recent investigations and findings regarding in vitro and animal model studies on the anti-inflammatory effects of fruits, vegetables, and food legumes. Specific cytokines released for specific type of physiological event might shed some light on the specific use of each source of phytochemicals that can benefit to counter the inflammatory response. As natural modulators of proinflammatory gene expressions, phytochemical from fruits, vegetables, and food legumes could be incorporated into novel bioactive anti-inflammatory formulations of various nutraceuticals and pharmaceuticals. Finally, these phytochemicals are discussed as the natural promotion strategy for the improvement of human health status. The phenolics and triterpenoids in fruits and vegetables showed higher anti-inflammatory activity than other compounds. In food legumes, lectins and peptides had anti-inflammatory activity in most cases. However, there are lack of human study data on the anti-inflammatory activity of phytochemicals from fruits, vegetables, and food legumes.

  14. Idiopathic Inflammatory Myopathies

    PubMed Central

    Barohn, Richard J.; Amato, Anthony

    2014-01-01

    The idiopathic inflammatory myopathies (IIM) consist of rare heterogenous autoimmune disorders that present with marked proximal and symmetric muscle weakness, except for distal and asymmetric weakness in inclusion body myositis (IBM). Besides frequent creatine kinase (CK) elevation, the electromyogram confirms the presence of an irritative myopathy. Extramuscular involvement affects a significant number of cases with interstitial lung disease (ILD), cutaneous in dermatomyositis (DM), systemic or joint manifestations and increased risk of malignancy especially in DM. Myositis specific autoantibodies influence phenotype of the IIM. Jo-1 antibodies are frequently associated with ILD and the newly described HMG-CoA reductase antibodies are characteristic of autoimmune necrotizing myopathy (NM). Muscle pathology ranges from inflammatory exudates of variable distribution, to intact muscle fiber invasion, necrosis, phagocytosis and in the case of IBM rimmed vacuoles and protein deposits. Despite many similarities, the IIM are a quite heterogeneous from the histopathological and pathogenetic standpoints in addition to some clinical and treatment-response difference. The field has witnessed significant advances in our understanding of pathophysiology and treatment of these rare disorders. In this review, we focus on DM, polymyositis (PM) and NM and examine current and promising therapies. The reader interested in more details on IBM is referred to the corresponding chapter in this issue. PMID:25037081

  15. The sterile inflammatory response.

    PubMed

    Rock, Kenneth L; Latz, Eicke; Ontiveros, Fernando; Kono, Hajime

    2010-01-01

    The acute inflammatory response is a double-edged sword. On the one hand, it plays a key role in initial host defense, particularly against many infections. On the other hand, its aim is imprecise, and as a consequence, when it is drawn into battle, it can cause collateral damage in tissues. In situations where the inciting stimulus is sterile, the cost-benefit ratio may be high; because of this, sterile inflammation underlies the pathogenesis of a number of diseases. Although there have been major advances in our understanding of how microbes trigger inflammation, much less has been learned about this process in sterile situations. This review focuses on a subset of the many sterile stimuli that can induce inflammation-specifically dead cells and a variety of irritant particles, including crystals, minerals, and protein aggregates. Although this subset of stimuli is structurally very diverse and might appear to be unrelated, there is accumulating evidence that the innate immune system may recognize them in similar ways and stimulate the sterile inflammatory response via common pathways. Here we review established and emerging data about these responses.

  16. [Inflammatory abdominal aortic aneurysm].

    PubMed

    Siebenmann, R; Schneider, K; von Segesser, L; Turina, M

    1988-06-11

    348 cases of abdominal aortic aneurysm were reviewed for typical features of inflammatory aneurysm (IAAA) (marked thickening of aneurysm wall, retroperitoneal fibrosis and rigid adherence of adjacent structures). IAAA was present in 15 cases (14 male, 1 female). When compared with patients who had ordinary aneurysms, significantly more patients complained of back or abdominal pain (p less than 0.01). Erythrocyte sedimentation rate was highly elevated. Diagnosis was established in 7 of 10 computed tomographies. 2 patients underwent emergency repair for ruptured aneurysm. Unilateral ureteral obstruction was present in 4 cases and bilateral in 1. Repair of IAAA was performed by a modified technique. Histological examination revealed thickening of the aortic wall, mainly of the adventitial layer, infiltrated by plasma cells and lymphocytes. One 71-year-old patient operated on for rupture of IAAA died early, and another 78-year-old patient after 5 1/2 months. Control computed tomographies revealed spontaneous regression of inflammatory infiltration after repair. Equally, hydronephrosis due to ureteral obstruction could be shown to disappear or at least to decrease. IAAA can be diagnosed by computed tomography with high sensitivity. Repair involves low risk, but modification of technique is necessary. The etiology of IAAA remains unclear.

  17. Inflammatory abdominal aortic aneurysm.

    PubMed

    Savarese, R P; Rosenfeld, J C; DeLaurentis, D A

    1986-05-01

    Between January 1976 and December 1982, 181 patients with abdominal aortic aneurysms were treated surgically, and in 13 patients the aneurysms were found to be inflammatory. Inflammatory aneurysms of the abdominal aorta (IAAA) share important characteristics with typical atherosclerotic abdominal aortic aneurysms. Diagnosis and surgical management of IAAA are distinctive which suggests that IAAA should be considered separately, as a varient of typical abdominal aortic aneurysms. IAAA occur predominantly in males. The presenting symptoms are often idiosyncratic and include severe abdominal or back pain, or both, and ureteral obstruction; the diagnosis of IAAA should be considered when these symptoms are present. Although grossly and microscopically, the perianeurysmal fibrosis resembles idiopathic retroperitoneal fibrosis, the two conditions can be differentiated. At the present time, ultrasonography and computed tomography appear to offer reliable means for diagnosing IAAA. The presence of IAAA, whether established preoperatively or discovered unexpectedly at operation, necessitate certain modifications in the surgical approach, in order to avoid injuring the duodenum and the venous structures. Most patients can be successfully treated by resection and graft replacement. Rupture of the aneurysm in IAAA appears to be less frequent than in typical atherosclerotic abdominal aortic aneurysm.

  18. Pelvic inflammatory disease.

    PubMed

    Soper, David E

    2010-08-01

    Pelvic inflammatory disease (PID) is an infection-caused inflammatory continuum from the cervix to the peritoneal cavity. Most importantly, it is associated with fallopian tube inflammation, which can lead to infertility, ectopic pregnancy, and chronic pelvic pain. The microbial etiology is linked to sexually transmitted microorganisms, including Chlamydia trachomatis, Neisseria gonorrheae, Mycoplasma genitalium, and bacterial vaginosis-associated microorganisms, predominantly anaerobes. Pelvic pain and fever are commonly absent in women with confirmed PID. Clinicians should consider milder symptoms such as abnormal vaginal discharge, metrorrhagia, postcoital bleeding, and urinary frequency as potential symptoms associated with the disease, particularly in women at risk of sexually transmitted infection. The diagnosis of PID is based on the findings of lower genital tract inflammation associated with pelvic organ tenderness. The outpatient treatment of mild-to-moderate PID should include tolerated antibiotic regimens with activity against the commonly isolated microorganisms associated with PID and usually consists of an extended spectrum cephalosporin in conjunction with either doxycycline or azithromycin. Clinically severe PID should prompt hospitalization and imaging to rule out a tuboovarian abscess. Parenteral broad-spectrum antibiotic therapy with activity against a polymicrobial flora, particularly gram-negative aerobes and anaerobes, should be implemented. Screening for and treatment of Chlamydia infection can prevent PID.

  19. Colon-targeted cell-permeable NFκB inhibitory peptide is orally active against experimental colitis.

    PubMed

    Hong, Sungchae; Yum, Soohwan; Yoo, Hyun-Jung; Kang, Sookjin; Yoon, Jeong-Hyun; Min, Dosik; Kim, Young Mi; Jung, Yunjin

    2012-05-07

    For the purpose of development of orally active peptide therapeutics targeting NFκB for treatment of inflammatory bowel disease (IBD), two major barriers in oral delivery of therapeutic peptides, metabolic lability and tissue impermeability, were circumvented by introduction of a colon-targeted delivery system and cell permeable peptides (CPP) to NFκB inhibitory peptides (NIP). Suppression of NFκB activation was compared following treatment with various CPP conjugated NIPs (CPP-NIP). The most potent CPP-NIP was loaded in a capsule coated with a colon specific polymer, which was administered orally to colitic rats. The anti-inflammatory activity of the colon-targeted CPP-NIP was evaluated by measuring inflammatory indices in the inflamed colonic tissue. For confirmation of the local action of the CPP-NIP, the same experiment was done after rectal administration. Tissue permeability of the CPP-NIP was examined microscopically and spectrophotometrically using FITC-labeled CPP-NIP (CPP-NIP-FITC). NEMO binding domain peptide (NBD, TALDWSWLQTE) fused with a cell permeable peptide CTP (YGRRARRRARR), CTP-NBD, was most potent in inhibiting NFκB activity in cells. Colon-targeted CTP-NBD, but not colon-targeted NBD and CTP-NBD in an enteric capsule, ameliorated the colonic injury, which was in parallel with decrease in MPO activity and the levels of inflammatory mediators. Intracolonic treatment with CTP-NBD alleviated rat colitis and improved all the inflammatory indicators. CTP-NBD-FITC was detected at much greater level in the inflamed tissue than was NBD-FITC. Taken together, introduction of cell permeability and colon targetability to NIP may be a feasible strategy for an orally active peptide therapy for treatment of IBD.

  20. Recognition of Bacterial Signal Peptides by Mammalian Formyl Peptide Receptors

    PubMed Central

    Bufe, Bernd; Schumann, Timo; Kappl, Reinhard; Bogeski, Ivan; Kummerow, Carsten; Podgórska, Marta; Smola, Sigrun; Hoth, Markus; Zufall, Frank

    2015-01-01

    Formyl peptide receptors (FPRs) are G-protein-coupled receptors that function as chemoattractant receptors in innate immune responses. Here we perform systematic structure-function analyses of FPRs from six mammalian species using structurally diverse FPR peptide agonists and identify a common set of conserved agonist properties with typical features of pathogen-associated molecular patterns. Guided by these results, we discover that bacterial signal peptides, normally used to translocate proteins across cytoplasmic membranes, are a vast family of natural FPR agonists. N-terminally formylated signal peptide fragments with variable sequence and length activate human and mouse FPR1 and FPR2 at low nanomolar concentrations, thus establishing FPR1 and FPR2 as sensitive and broad signal peptide receptors. The vomeronasal receptor mFpr-rs1 and its sequence orthologue hFPR3 also react to signal peptides but are much more narrowly tuned in signal peptide recognition. Furthermore, all signal peptides examined here function as potent activators of the innate immune system. They elicit robust, FPR-dependent calcium mobilization in human and mouse leukocytes and trigger a range of classical innate defense mechanisms, such as the production of reactive oxygen species, metalloprotease release, and chemotaxis. Thus, bacterial signal peptides constitute a novel class of immune activators that are likely to contribute to mammalian immune defense against bacteria. This evolutionarily conserved detection mechanism combines structural promiscuity with high specificity and enables discrimination between bacterial and eukaryotic signal sequences. With at least 175,542 predicted sequences, bacterial signal peptides represent the largest and structurally most heterogeneous class of G-protein-coupled receptor agonists currently known for the innate immune system. PMID:25605714

  1. Chemokine CCR3 ligands-binding peptides derived from a random phage-epitope library.

    PubMed

    Houimel, Mehdi; Mazzucchelli, Luca

    2013-01-01

    Eosinophils are major effectors cells implicated in a number of chronic inflammatory diseases in humans, particularly bronchial asthma and allergic rhinitis. The human chemokine receptor C-C receptor 3 (hCCR3) provides a mechanism for the recruitment of eosinophils into tissue and thus has recently become an attractive biological target for therapeutic intervention. In order to develop peptides antagonists of hCCR3-hCCL11 (human eotaxin) interactions, a random bacteriophage hexapeptide library was used to map structural features of hCCR3 by determining the epitopes of neutralizing anti-hCCR3 mAb 7B11. This mAb t is selective for hCCR3 and exhibit potent antagonist activity in receptor binding and functional assays. After three rounds of biopanning, four mAb7B11-binding peptides were identified from a 6-mer linear peptide library. The phage bearing the peptides showed specific binding to immobilized mAb 7B11 with over 94% of phages bound being competitively inhibited by free synthetic peptides. In FACScan analysis all selected phage peptides were able to strongly inhibit the binding of mAb 7B11 to hCCR3-transfected preB-300-19 murine cells. Furthermore, synthetic peptides of the corresponding phage epitopes were effective in blocking the antibody-hCCR3 interactions and to inhibit the binding of hCCL11 to hCCR3 transfectants. Chemically synthesized peptides CKGERF, FERKGK, SSMKVK and RHVSSQ, effectively competed for (125)I-hCCL11 binding to hCCR3 with IC(50) ranging from 3.5 to 9.7μM. Calcium release and chemotaxis of hCCR3 transfectants or human eosinophils were inhibited by all peptides in a dose-dependent manner. Furthermore, they showed inhibitory effects on chemotaxis of human eosinophils induced by hCCL11, hCCL5, hCCL7, hCCL8, and hCCL24. Specificities of all selected peptides were assessed with hCXCR1, hCXCR2, hCXCR3, and hCCR5 receptors. Peptides CKGERF and FERKGK showed inhibitory effects on eosinophil chemotaxis in a murine model of mCCL11-induced

  2. Urinary Peptides in Rett Syndrome.

    ERIC Educational Resources Information Center

    Solaas, K. M.; Skjeldal, O.; Gardner, M. L. G.; Kase, B. F.; Reichelt, K. L.

    2002-01-01

    A study found a significantly higher level of peptides in the urine of 53 girls with Rett syndrome compared with controls. The elevation was similar to that in 35 girls with infantile autism. Levels of peptides were lower in girls with classic Rett syndrome than those with congenital Rett syndrome. (Contains references.) (Author/CR)

  3. Clinical uses of gut peptides.

    PubMed Central

    Geoghegan, J; Pappas, T N

    1997-01-01

    OBJECTIVE: The authors review clinical applications of gut-derived peptides as diagnostic and therapeutic agents. SUMMARY BACKGROUND DATA: An increasing number of gut peptides have been evaluated for clinical use. Earlier uses as diagnostic agents have been complemented more recently by increasing application of gut peptides as therapeutic agents. METHOD: The authors conducted a literature review. RESULTS: Current experience with clinical use of gut peptides is described. Initial clinical applications focused on using secretomotor effects of gut peptides in diagnostic tests, many of which have now fallen into disuse. More recently, attention has been directed toward harnessing these secretomotor effects for therapeutic use in a variety of disorders, and also using the trophic effects of gut peptides to modulate gut mucosal growth in benign and malignant disease. Gut peptides have been evaluated in a variety of other clinical situations including use as adjuncts to imaging techniques, and modification of behaviors such as feeding and panic disorder. CONCLUSIONS: Gut peptides have been used successfully in an increasing variety of clinical conditions. Further refinements in analogue and antagonist design are likely to lead to even more selective agents that may have important clinical applications. Further studies are needed to identity and evaluate these new agents. PMID:9065291

  4. Urinary Peptides in Rett Syndrome.

    ERIC Educational Resources Information Center

    Solaas, K. M.; Skjeldal, O.; Gardner, M. L. G.; Kase, B. F.; Reichelt, K. L.

    2002-01-01

    A study found a significantly higher level of peptides in the urine of 53 girls with Rett syndrome compared with controls. The elevation was similar to that in 35 girls with infantile autism. Levels of peptides were lower in girls with classic Rett syndrome than those with congenital Rett syndrome. (Contains references.) (Author/CR)

  5. Systematic screening for bioactive peptides.

    PubMed

    Maeji, N J; Bray, A M; Valerio, R M; Seldon, M A; Wang, J X; Geysen, H M

    1991-01-01

    Using simultaneous multiple peptide synthesis by the multipin approach, the feasibility of systematic large-scale pharmacological screening of peptide ligands was investigated. The method involves the assembly of small quantities of peptides (ca. 50 nmol) on plastic pins derivatized with an ester linker based on glycolate and 4-(hydroxymethyl)benzoate. These esters are stable under peptide synthesis and side-chain deprotection conditions but cleave under relatively mild basic conditions to generate peptides having C-terminal acid, amide and methylamide. A two-step approach to side-chain deprotection and cleavage from the solid support allows potentially toxic reagents to be removed (washed) from the peptide prior to cleavage. Consequently, the resulting peptide solutions can be used in bioassays with minimal processing. A series of angiotensin II and substance P analogs were synthesized and evaluated in an in vivo rat model and in vitro radioreceptor assay, respectively. Structure-activity studies on analogs of these bioactive peptides are well documented. The data obtained were consistent with that reported in the literature.

  6. Immunogenetics of ocular inflammatory disease.

    PubMed

    Levinson, R D

    2007-02-01

    Ocular inflammatory disease comprises of a diverse group of clinical entities that may result from autoimmune processes, infections, or both. While many individual ocular inflammatory diseases are quite rare, ocular inflammation is one of the more common causes of visual disability, including blindness, in the developed world. Better understanding of ocular inflammatory disease is an important step in designing more sophisticated therapies that may help prevent loss of visual function for these patients.

  7. Microscopic characterization of peptide nanostructures.

    PubMed

    Mammadov, Rashad; Tekinay, Ayse B; Dana, Aykutlu; Guler, Mustafa O

    2012-02-01

    Peptide-based nanomaterials have been utilized for various applications from regenerative medicine to electronics since they provide several advantages including easy synthesis methods, numerous routes for functionalization and biomimicry of secondary structures of proteins which leads to design of self-assembling peptide molecules to form nanostructures. Microscopic characterization at nanoscale is critical to understand processes directing peptide molecules to self-assemble and identify structure-function relationship of the nanostructures. Here, fundamental studies in microscopic characterization of peptide nanostructures are discussed to provide insights in widely used microscopy tools. In this review, we will encompass characterization studies of peptide nanostructures with modern microscopes, such as TEM, SEM, AFM, and advanced optical microscopy techniques. We will also mention specimen preparation methods and describe interpretation of the images.

  8. Bioactive peptides derived from food.

    PubMed

    Rutherfurd-Markwick, Kay J; Moughan, Paul J

    2005-01-01

    As interest in the ability of functional foods to impact on human health has grown over the past decade, so has the volume of knowledge detailing the beneficial roles of food-derived bioactive peptides. Bioactive peptides from both plant and animal proteins have been discovered, with to date, by far the most being isolated from milk-based products. A wide range of activities has been described, including antimicrobial and antifungal properties, blood pressure-lowering effects, cholesterol-lowering ability, antithrombotic effects, enhancement of mineral absorption, immunomodulatory effects, and localized effects on the gut. Although there is still considerable research to be performed in the area of food-derived bioactive peptides, it is clear that the generation of bioactive peptides from dietary proteins during the normal digestive process is of importance. Therefore, it will become necessary when determining dietary protein quality to consider the potential effects of latent bioactive peptides that are released during digestion of the protein.

  9. Peptides and peptidomimetics as immunomodulators

    PubMed Central

    Gokhale, Ameya S; Satyanarayanajois, Seetharama

    2014-01-01

    Peptides and peptidomimetics can function as immunomodulating agents by either blocking the immune response or stimulating the immune response to generate tolerance. Knowledge of B- or T-cell epitopes along with conformational constraints is important in the design of peptide-based immunomodulating agents. Work on the conformational aspects of peptides, synthesis and modified amino acid side chains have contributed to the development of a new generation of therapeutic agents for autoimmune diseases and cancer. The design of peptides/peptidomimetics for immunomodulation in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, systemic lupus and HIV infection is reviewed. In cancer therapy, peptide epitopes are used in such a way that the body is trained to recognize and fight the cancer cells locally as well as systemically. PMID:25186605

  10. Food derived bioactive peptides and intestinal barrier function.

    PubMed

    Martínez-Augustin, Olga; Rivero-Gutiérrez, Belén; Mascaraque, Cristina; Sánchez de Medina, Fermín

    2014-12-09

    A wide range of food-derived bioactive peptides have been shown to exert health-promoting actions and are therefore considered functional foods or nutraceuticals. Some of these actions are related to the maintenance, reinforcement or repairment of the intestinal barrier function (IBF) whose role is to selectively allow the absorption of water, nutrients and ions while preventing the influx of microorganisms from the intestinal lumen. Alterations in the IBF have been related to many disorders, such as inflammatory bowel disease or metabolic syndrome. Components of IBF are the intestinal epithelium, the mucus layer, secretory immunoglobulin A and cells of the innate and adaptive immune systems. Here we review the effects of food derived bioactive peptides on these IBF components. In vitro and in vivo effects, both in healthy and disease states, have been reviewed. Although limited, the available information indicates a potential for food-derived peptides to modify IBF and to contribute to disease treatment, but further research is needed to better isolate responsible peptides, and to help define their mode of action.

  11. Food Derived Bioactive Peptides and Intestinal Barrier Function

    PubMed Central

    Martínez-Augustin, Olga; Rivero-Gutiérrez, Belén; Mascaraque, Cristina; Sánchez de Medina, Fermín

    2014-01-01

    A wide range of food-derived bioactive peptides have been shown to exert health-promoting actions and are therefore considered functional foods or nutraceuticals. Some of these actions are related to the maintenance, reinforcement or repairment of the intestinal barrier function (IBF) whose role is to selectively allow the absorption of water, nutrients and ions while preventing the influx of microorganisms from the intestinal lumen. Alterations in the IBF have been related to many disorders, such as inflammatory bowel disease or metabolic syndrome. Components of IBF are the intestinal epithelium, the mucus layer, secretory immunoglobulin A and cells of the innate and adaptive immune systems. Here we review the effects of food derived bioactive peptides on these IBF components. In vitro and in vivo effects, both in healthy and disease states, have been reviewed. Although limited, the available information indicates a potential for food-derived peptides to modify IBF and to contribute to disease treatment, but further research is needed to better isolate responsible peptides, and to help define their mode of action. PMID:25501338

  12. Tat-Mediated Peptide Intervention in Analgesia and Anesthesia

    PubMed Central

    Tao, Feng; Johns, Roger A.

    2010-01-01

    Membrane-permeable peptide carriers are attractive drug delivery tools. Among such carriers, the protein transduction domain (PTD) of the human immunodeficiency virus-type 1 Tat protein is most frequently used and has been successfully shown to deliver a large variety of cargoes. The Tat PTD can facilitate the uptake of large, biologically active molecules into mammalian cells, and recent studies have shown that it can mediate the delivery of different cargoes into tissues throughout a living organism. Given that the Tat PTD-mediated delivery is size-independent, this technology could make previously non-applicable large molecules usable to modulate biological function in vivo and treat human diseases. It is likely that the peptide carrier-mediated intracellular delivery process encompasses multiple mechanisms, but endocytic pathways are the predominant internalization routes. Tat PTD has been successfully used in preclinical models for the study of cancer, ischemia, inflammation, analgesia, and anesthesia. Our recent studies have shown that intraperitoneally injected fusion Tat peptide Tat-PSD-95 PDZ2 can be delivered into the spinal cord to dose-dependently disrupt protein-protein interactions between PSD-95 and NMDA receptors. This peptide significantly inhibits chronic inflammatory pain and reduces the threshold for halothane anesthesia. The ability of the Tat PTD to target any cell is advantageous in some respects. However, the drug delivery system will be more attractive if we can modify the Tat PTD to deliver cargo only into desired organs to avoid possible side effects. PMID:20711510

  13. Osteoporosis in Inflammatory Bowel Disease

    PubMed Central

    Ali, Tauseef; Lam, David; Bronze, Michael S.; Humphrey, Mary Beth

    2010-01-01

    Osteoporosis commonly afflicts patients with inflammatory bowel disease, and many factors link the 2 states together. A literature review was conducted about the pathophysiology of osteoporosis in relation to inflammatory bowel disease. Screening guidelines for osteoporosis in general as well as those directed at patients with inflammatory bowel disease are reviewed, as are currently available treatment options. The purpose of this article is to increase physician awareness about osteopenia and osteoporosis occurring in patients with inflammatory bowel disease and to provide basic, clinically relevant information about the pathophysiology and guidelines to help them treat these patients in a cost-effective manner. PMID:19559158

  14. Salivary Antimicrobial Peptides in Early Detection of Periodontitis

    PubMed Central

    Güncü, Güliz N.; Yilmaz, Dogukan; Könönen, Eija; Gürsoy, Ulvi K.

    2015-01-01

    In the pathogenesis of periodontitis, an infection-induced inflammatory disease of the tooth-supporting tissues, there is a complex interaction between the subgingival microbiota and host tissues. A periodontal diagnostic tool for detecting the initiation and progression of the disease, monitoring the response to therapy, or measuring the degree of susceptibility to future disease progression has been of interest for a long time. The value of various enzymes, proteins, and immunoglobulins, which are abundant constituents of saliva, as potential biomarkers has been recognized and extensively investigated for periodontal diseases. Gingival defensins and cathelicidins are small cationic antimicrobial peptides that play an important role in innate immune response. However, their applicability as salivary biomarkers is still under debate. The present review focuses on proteomic biomarkers and antimicrobial peptides, in particular, to be used at early phases of periodontitis. PMID:26734583

  15. Autophagy impairment by caspase-1-dependent inflammation mediates memory loss in response to β-Amyloid peptide accumulation.

    PubMed

    Álvarez-Arellano, Lourdes; Pedraza-Escalona, Martha; Blanco-Ayala, Tonali; Camacho-Concha, Nohemí; Cortés-Mendoza, Javier; Pérez-Martínez, Leonor; Pedraza-Alva, Gustavo

    2017-08-12

    β-Amyloid peptide accumulation in the cortex and in the hippocampus results in neurodegeneration and memory loss. Recently, it became evident that the inflammatory response triggered by β-Amyloid peptides promotes neuronal cell death and degeneration. In addition to inflammation, β-Amyloid peptides also induce alterations in neuronal autophagy, eventually leading to neuronal cell death. Thus, here we evaluated whether the inflammatory response induced by the β-Amyloid peptides impairs memory via disrupting the autophagic flux. We show that male mice overexpressing β-Amyloid peptides (5XFAD) but lacking caspase-1, presented reduced β-Amyloid plaques in the cortex and in the hippocampus; restored brain autophagic flux and improved learning and memory capacity. At the molecular level, inhibition of the inflammatory response in the 5XFAD mice restored LC3-II levels and prevented the accumulation of oligomeric p62 and ubiquitylated proteins. Furthermore, caspase-1 deficiency reinstates activation of the AMPK/Raptor pathway while down-regulating AKT/mTOR pathway. Consistent with this, we found an inverse correlation between the increase of autophagolysosomes in the cortex of 5XFAD mice lacking caspase-1 and the presence of mitochondria with altered morphology. Together our results indicate that β-Amyloid peptide-induced caspase-1 activation, disrupts autophagy in the cortex and in the hippocampus resulting in neurodegeneration and memory loss. © 2017 Wiley Periodicals, Inc.

  16. "Potential health benefits of lunasin: a multifaceted soy-derived bioactive peptide".

    PubMed

    Lule, Vaibhao Kisanrao; Garg, Sheenam; Pophaly, Sarang Dilip; Hitesh; Tomar, Sudhir Kumar

    2015-03-01

    Bioactive peptides are small protein fragments derived from enzymatic hydrolysis of food proteins, fermentation with proteolytic starter cultures, and gastrointestinal digestion. These peptides have positive impacts on a number of physiological functions in living beings. Lunasin, a soy-derived bioactive peptide, is one of the most promising among them. Lunasin encoded within 2S albumin (GM2S-1) gene, identified as a novel peptide extracted from soybean seed. It is composed of 43 amino acid residues with a molecular weight of 5.5 kDa. Extensive scientific studies have shown that lunasin possesses inherent antioxidative, anti-inflammatory, anticancerous properties and could also play a vital role in regulating of cholesterol biosynthesis in the body. Its high bioavailability and heat stable nature allow its potential use as dietary supplement. The present review summarizes some of the potential health and therapeutic benefits of lunasin reported hitherto. © 2015 Institute of Food Technologists®

  17. Defense peptides secreted by helminth pathogens: antimicrobial and/or immunomodulator molecules?

    PubMed Central

    Cotton, Sophie; Donnelly, Sheila; Robinson, Mark W.; Dalton, John P.; Thivierge, Karine

    2012-01-01

    Host defense peptides (HDPs) are an evolutionarily conserved component of the innate immune response found in all living species. They possess antimicrobial activities against a broad range of organisms including bacteria, fungi, eukaryotic parasites, and viruses. HDPs also have the ability to enhance immune responses by acting as immunomodulators. We discovered a new family of HDPs derived from pathogenic helminth (worms) that cause enormous disease in animals and humans worldwide. The discovery of these peptides was based on their similar biochemical and functional characteristics to the human defense peptide LL-37. We propose that these new peptides modulate the immune response via molecular mimicry of mammalian HDPs thus providing a mechanism behind the anti-inflammatory properties of helminth infections. PMID:22973271

  18. Fatal inflammatory hypophysitis.

    PubMed

    McIntyre, Elizabeth A; Perros, Petros

    2007-01-01

    A young female patient presented as an acute medical emergency with hypoglycaemia. Investigations revealed panhypopituitarism and an inflammatory pituitary mass. An antibody screen was negative for anti-neutrophil cytoplasmic antibodies with cytoplasmic distribution (cANCA). Pituitary histology showed lymphocytic infiltration and a few Langerhan's cells. The pituitary mass rapidly expanded to involve the optic nerves and led to bilateral blindness. Later, the patient developed diarrhoea, a vasculitis rash, scleritis, and proteinuria. In subsequent investigations cANCA became positive. The patient responded to steroids and cyclophosphamide treatment and remained in partial remission for six months before dying of severe sepsis. This is the first description of Wegener's granulomatosis presenting with acute anterior pituitary failure in the absence of other organ involvement and negative serology.

  19. [Inflammatory abdominal aortic aneurysm].

    PubMed

    Mikami, Y; Kyogoku, M

    1994-08-01

    Inflammatory abdominal aortic aneurysm (IAAA) is a distinct clinicopathological entity, characterized by: (1) clinical presentation, such as back pain, weight loss, and increased ESR, (2) patchy and/or diffuse lymphoplasmacytic infiltration, and (3) marked periaortic fibrosis resulting in thickening of the aneurysmal wall and occasional retroperitoneal fibrosis. Its pathogenesis is unknown, but some authors support the theory that IAAA is a subtype of atherosclerotic abdominal aortic aneurysm because of close relationship between IAAA and atherosclerotic change. In this article, we describe clinical and histological features of IAAA on the basis of the literature and our review of 6 cases of IAAA, emphasizing the similarity and difference between IAAA and atherosclerotic abdominal aortic aneurysm. Our review supports that marked lamellar fibrosis completely replacing the media and adventitia, patchy lymphocytic infiltration (mostly B cells) and endarteritis obliterans are characteristic features of IAAA.

  20. Inflammatory Bowel Disease

    PubMed Central

    Nasseri-Moghaddam, Siavosh

    2012-01-01

    Inflammatory bowel disease (IBD) is the term used for a group of diseases with yet unknown etiology, prevalence of which is increasing almost everywhere in the world. The disease was almost non-existent four decades ago in the east, including the middle-east, while now a days it is seen more and more. In addition to the increasing prevalence, our knowledge about its pathogenesis, clinical course, diagnosis, and treatment has changed dramatically over the past couple of decades. This has changed our concept of this group of diseases, their diagnosis, treatment, and treatment goals. Considering the vast literature on the subject, it is timely to review major topics in IBD with a look on the regional progress and knowledge as well. This essay is aimed to cover this task. PMID:24829639

  1. The promotion of functional urinary bladder regeneration using anti-inflammatory nanofibers

    PubMed Central

    Bury, Matthew I.; Fuller, Natalie J.; Meisner, Jay W.; Hofer, Matthias D.; Webber, Matthew J.; Chow, Lesley W.; Prasad, Sheba; Thaker, Hatim; Yue, Xuan; Menon, Vani S.; Diaz, Edward C.; Stupp, Samuel I.; Cheng, Earl Y.; Sharma, Arun K.

    2014-01-01

    Current attempts at tissue regeneration utilizing synthetic and decellularized biologic-based materials have typically been met in part by innate immune responses in the form of a robust inflammatory reaction at the site of implantation or grafting. This can ultimately lead to tissue fibrosis with direct negative impact on tissue growth, development, and function. In order to temper the innate inflammatory response, anti-inflammatory signals were incorporated through display on self-assembling peptide nanofibers to promote tissue healing and subsequent graft compliance throughout the regenerative process. Utilizing an established urinary bladder augmentation model, the highly pro-inflammatory biologic scaffold (decellularized small intestinal submucosa) was treated with anti-inflammatory peptide amphiphiles (AIF-PAs) or control peptide amphiphiles and used for augmentation. Significant regenerative advantages of the AIF-PAs were observed including potent angiogenic responses, limited tissue collagen accumulation, and the modulation of macrophage and neutrophil responses in regenerated bladder tissue. Upon further characterization, a reduction in the levels of M2 macrophages was observed, but not in M1 macrophages in control groups, while treatment groups exhibited decreased levels of M1 macrophages and stabilized levels of M2 macrophages. Pro-inflammatory cytokine production was decreased while anti-inflammatory cytokines were up-regulated in treatment groups. This resulted in far fewer incidences of tissue granuloma and bladder stone formation. Finally, functional urinary bladder testing revealed greater bladder compliance and similar capacities in groups treated with AIF-PAs. Data demonstrate that AIF-PAs can alleviate galvanic innate immune responses and provide a highly conducive regenerative milieu that may be applicable in a variety of clinical settings. PMID:25145852

  2. Antimicrobial peptides: therapeutic potentials.

    PubMed

    Kang, Su-Jin; Park, Sung Jean; Mishig-Ochir, Tsogbadrakh; Lee, Bong-Jin

    2014-12-01

    The increasing appearance of multidrug-resistant pathogens has created an urgent need for suitable alternatives to current antibiotics. Antimicrobial peptides (AMPs), which act as defensive weapons against microbes, have received great attention because of broad-spectrum activities, unique action mechanisms and rare antibiotic-resistant variants. Despite desirable characteristics, they have shown limitations in pharmaceutical development due to toxicity, stability and manufacturing costs. Because of these drawbacks, only a few AMPs have been tested in Phase III clinical trials and no AMPs have been approved by the US FDA yet. However, these obstacles could be overcome by well-known methods such as changing physicochemical characteristics and introducing nonnatural amino acids, acetylation or amidation, as well as modern techniques like molecular targeted AMPs, liposomal formulations and drug delivery systems. Thus, the current challenge in this field is to develop therapeutic AMPs at a reasonable cost as well as to overcome the limitations.

  3. Asymmetric Peptide Nanoribbons.

    PubMed

    Yu, Zhilin; Tantakitti, Faifan; Palmer, Liam C; Stupp, Samuel I

    2016-11-09

    Asymmetry in chemical structure or shape at molecular, nanoscale, or microscopic levels is essential to a vast number of functionalities in both natural and artificial systems. Bottom-up approaches to create asymmetric supramolecular nanostructures are considered promising but this strategy suffers from the potentially dynamic nature of noncovalent interactions. We report here on supramolecular self-assembly of asymmetric peptide amphiphiles consisting of two different molecularly linked domains. We found that strong noncovalent interactions and a high degree of internal order among the asymmetric amphiphiles lead to nanoribbons with asymmetric faces due to the preferential self-association of the two domains. The capture of gold nanoparticles on only one face of the nanoribbons demonstrates symmetry breaking in these supramolecular structures.

  4. [Anti-cyclic citrullinated peptide antibodies and rheumatoid arthritis].

    PubMed

    Hayashi, Nobuhide; Kumagai, Shunichi

    2010-05-01

    Rheumatoid arthritis (RA) is a severe, progressive, systemic inflammatory disease of unknown etiology. Early diagnosis of RA is important to identify individuals who will develop severe destructive disease, so that effective treatment can be initiated before irreversible damage occurs. Rheumatoid factor (RF) has been commonly used as a serological marker for RA, although RF had a tolerable sensitivity of 75.9% for RA, but low specificity of 78.7% and 75.4% for patients with other rheumatic diseases and chronic inflammatory disease, respectively. Antibodies to citrullinated protein/peptide antigens, i.e., to peptides post-translationally modified by the conversion of arginine to cilrulline (ACPA), are specific serological markers for RA. Not only did anti-cyclic citrullinated peptide antibody (anti-CCP) demonstrate a higher sensitivity of 78.5% when compared to RF, but anti-CCP also had a much higher specificity of 95.9% and 97.9% for other rheumatic diseases and chronic inflammatory disease patients, respectively. Moreover, meta-analysis revealed that pooled sensitivity and pooled specificity were 67% and 95% for anti-CCP, 69% and 85% for RF, respectively, and that anti-CCP was more specific than RF for diagnosing RA. In 2009, ACPA (anti-CCP) was included in the new Criteria for RA from the American College of Rheumatology and the European League Against Rheumatism. Anti-CCP testing is particularly useful in the diagnosis of RA, being present early in the disease process, and able to predict severe disease and irreversible damage. In addition, the titers might be early predictors of the efficacy of anti-TNF therapy. In this review, we discuss the historical background of anti-CCP as well as its diagnostic performance, usefulness for early diagnosis, prognostic capability, and pathogenesis of RA.

  5. Short Antimicrobial Peptides and Peptide Scaffolds as Promising Antibacterial Agents.

    PubMed

    Domalaon, Ronald; Zhanel, George G; Schweizer, Frank

    2016-01-01

    Antimicrobial peptides have recently garnered significant attention as an emerging source of potential antibiotics, due to the swift emergence of multidrug-resistant bacteria and a dwindling antibiotic pipeline. The vast majority of antimicrobial peptides are long, comprised of more than 10 amino acids, resulting in significant production costs for their synthesis while simultaneously displaying metabolic instability and relatively poor pharmacological profiles. To counter these problems, efforts have been shifted to shorter molecules and the development of new peptidomimetic approaches. In this paper, we review promising short, naturally-isolated or synthetic, antimicrobial peptides, along with their mimics, and discuss their merits as potential antibacterial agents.

  6. Peptide-formation on cysteine-containing peptide scaffolds

    NASA Technical Reports Server (NTRS)

    Chu, B. C.; Orgel, L. E.

    1999-01-01

    Monomeric cysteine residues attached to cysteine-containing peptides by disulfide bonds can be activated by carbonyldiimidazole. If two monomeric cysteine residues, attached to a 'scaffold' peptide Gly-Cys-Glyn-Cys-Glu10, (n = 0, 1, 2, 3) are activated, they react to form the dipeptide Cys-Cys. in 25-65% yield. Similarly, the activation of a cysteine residue attached to the 'scaffold' peptide Gly-Cys-Gly-Glu10 in the presence of Arg5 leads to the formation of Cys-Arg5 in 50% yield. The significance of these results for prebiotic chemistry is discussed.

  7. Anti-proline-glycine-proline or antielastin autoantibodies are not evident in chronic inflammatory lung disease.

    PubMed

    Greene, Catherine M; Low, Teck Boon; O'Neill, Shane J; McElvaney, Noel G

    2010-01-01

    In patients with chronic inflammatory lung disease, pulmonary proteases can generate neoantigens from elastin and collagen with the potential to fuel autoreactive immune responses. Antielastin peptide antibodies have been implicated in the pathogenesis of tobacco-smoke-induced emphysema. Collagen-derived peptides may also play a role. To determine whether autoantibodies directed against elastin- and collagen-derived peptides are present in plasma from three groups of patients with chronic inflammatory lung disease compared with a nonsmoking healthy control group and to identify whether autoimmune responses to these peptides may be an important component of the disease process in these patients. A total of 124 patients or healthy control subjects were recruited for the study (Z-A1AT deficiency, n = 20; cystic fibrosis, n = 40; chronic obstructive pulmonary disease, n = 31; healthy control, n = 33). C-reactive protein, IL-32, and antinuclear antibodies were quantified. Antielastin and anti-N-acetylated-proline-glycine-proline autoantibodies were measured by reverse ELISA. All patients were deemed stable and noninfective on the basis of the absence of clinical or radiographic evidence of recent infection. There were no significant differences in the levels of autoantibodies or IL-32 in the patients groups compared with the healthy control subjects. Antielastin or anti-N-acetylated proline-glycine-proline autoantibodies are not evident in chronic inflammatory lung disease.

  8. Cathelicidin-related antimicrobial peptide modulates the severity of acute pancreatitis in mice

    PubMed Central

    DENG, YUAN-YUAN; SHAMOON, MUHAMMAD; HE, YUE; BHATIA, MADHAV; SUN, JIA

    2016-01-01

    The present study aimed to investigate the immunomodulatory effects of mouse cathelicidin-related antimicrobial peptide (CRAMP) on experimental acute pancreatitis (AP). AP is a common clinical condition characterized by acute abdominal inflammation. Innate immune cells and mediators are intrinsically linked to the pathogenesis of AP. Cathelicidins are innate immunity-derived antimicrobial peptides that exert immunomodulatory effects on various host cells. However, how cathelicidins are involved and modulate the severity and inflammatory responses of AP remains unclear. In the present study, the mouse CRAMP gene-deficient cnlp−/− mice and their wild-type C57BL/6J littermates were induced with AP by multiple hourly injections of supramaximal doses of caerulein. Serum amylase levels, pancreatic myeloperoxidase activity and histological examination were performed in order to determine the disease severity and the levels of inflammatory cytokines. Disease severity and inflammatory markers were subsequently evaluated in the control mice, cnlp−/− C57BL/6J mice with AP, and wild-type C57BL/6J mice with AP. The results demonstrated that cnlp−/− mice exhibited a more severe phenotype and inflammatory response following AP induction compared with the wild-type mice, as evidenced by increased serum amylase levels, pancreatic myeloperoxidase release, and early inflammatory mediator tumor necrosis factor-α production. Histological examination confirmed that CRAMP deficiency worsened the pancreatic inflammatory condition. These results indicate that CRAMP may be considered a novel modulatory mediator in mouse experimental AP. PMID:27035328

  9. Resistance to endotoxic shock in mice lacking natriuretic peptide receptor-A.

    PubMed

    Panayiotou, Catherine M; Baliga, Reshma; Stidwill, Raymond; Taylor, Valerie; Singer, Mervyn; Hobbs, Adrian J

    2010-08-01

    Excessive production of nitric oxide (NO) by inducible NO synthase (iNOS) is thought to underlie the vascular dysfunction, systemic hypotension and organ failure that characterize endotoxic shock. Plasma levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) are raised in animal models and humans with endotoxic shock and correlate with the associated cardiovascular dysfunction. Since both NO and natriuretic peptides play important roles in cardiovascular homeostasis via activation of guanylate cyclase-linked receptors, we used mice lacking natriuretic peptide receptor (NPR)-A (NPR1) to establish if natriuretic peptides contribute to the cardiovascular dysfunction present in endotoxic shock. Wild-type (WT) and NPR-A knockout (KO) mice were exposed to lipopolysaccharide (LPS) and vascular dysfunction (in vitro and in vivo), production of pro-inflammatory cytokines, and iNOS expression and activity were evaluated. LPS-treated WT animals exhibited a marked fall in mean arterial blood pressure (MABP) whereas NPR-A KO mice maintained MABP throughout. LPS administration caused a greater suppression of vascular responses to the thromboxane-mimetic U46619, ANP, acetylcholine and the NO-donor spermine-NONOate in WT versus NPR-A KO mice. This differential effect on vascular function was paralleled by reduced pro-inflammatory cytokine production, iNOS expression and activity (plasma [NO(x)] and cyclic GMP). These observations suggest that NPR-A activation by natriuretic peptides facilitates iNOS expression and contributes to the vascular dysfunction characteristic of endotoxic shock. Pharmacological interventions that target the natriuretic peptide system may represent a novel approach to treat this life-threatening condition.

  10. A TLR4-interacting SPA4 peptide inhibits LPS-induced lung inflammation.

    PubMed

    Ramani, Vijay; Madhusoodhanan, Rakhesh; Kosanke, Stanley; Awasthi, Shanjana

    2013-12-01

    The interaction between surfactant protein-A (SP-A) and TLR4 is important for host defense. We have recently identified an SPA4 peptide region from the interface of SP-A-TLR4 complex. Here, we studied the involvement of the SPA4 peptide region in SP-A-TLR4 interaction using a two-hybrid system, and biological effects of SPA4 peptide in cell systems and a mouse model. HEK293 cells were transfected with plasmid DNAs encoding SP-A or a SP-A-mutant lacking SPA4 peptide region and TLR4. Luciferase activity was measured as the end-point of SP-A-TLR4 interaction. NF-κB activity was also assessed simultaneously. Next, the dendritic cells or mice were challenged with Escherichia coli-derived LPS and treated with SPA4 peptide. Endotoxic shock-like symptoms and inflammatory parameters (TNF-α, NF-κB, leukocyte influx) were assessed. Our results reveal that the SPA4 peptide region contributes to the SP-A-TLR4 interaction and inhibits the LPS-induced NF-κB activity and TNF-α. We also observed that the SPA4 peptide inhibits LPS-induced expression of TNF-α, nuclear localization of NF-κB-p65 and cell influx, and alleviates the endotoxic shock-like symptoms in a mouse model. Our results suggest that the anti-inflammatory activity of the SPA4 peptide through its binding to TLR4 can be of therapeutic benefit.

  11. The therapeutic applications of antimicrobial peptides (AMPs): a patent review.

    PubMed

    Kang, Hee-Kyoung; Kim, Cheolmin; Seo, Chang Ho; Park, Yoonkyung

    2017-01-01

    Antimicrobial peptides (AMPs) are small molecules with a broad spectrum of antibiotic activities against bacteria, yeasts, fungi, and viruses and cytotoxic activity on cancer cells, in addition to anti-inflammatory and immunomodulatory activities. Therefore, AMPs have garnered interest as novel therapeutic agents. Because of the rapid increase in drug-resistant pathogenic microorganisms, AMPs from synthetic and natural sources have been developed using alternative antimicrobial strategies. This article presents a broad analysis of patents referring to the therapeutic applications of AMPs since 2009. The review focuses on the universal trends in the effective design, mechanism, and biological evolution of AMPs.

  12. Endomorphins as agents for the treatment of chronic inflammatory disease.

    PubMed

    Jessop, David S

    2006-01-01

    Endomorphin (EM)-1 and EM-2 are tetrapeptides located within the mammalian central nervous system and immune tissues, with high affinity and specificity for micro-opioid receptors. Most of the literature has focused on the analgesic properties of EM-1 and EM-2 in animal models of neuropathic or neurogenic pain, but there is persuasive evidence emerging that EMs can also exert potent anti-inflammatory effects in both acute and chronic peripheral inflammation. The purpose of this review is to present and evaluate the evidence for anti-inflammatory properties of EM-1 and EM-2 with a view to their potential for use in chronic human inflammatory disease. Distribution of EMs within the immune system and functional roles as immunomodulatory agents are summarized and discussed. Possible milestones to be met revolve around issues of peptide stability, biodegradability problems and optimal route and method of delivery. The potential for delivery of a low-cost drug with both peripheral anti-inflammatory and analgesic properties, effective in low doses, and targeted to the site of inflammation, should focus our attention on further development of EMs as potent therapeutic agents in chronic inflammation.

  13. Mechanisms of immunological tolerance in central nervous system inflammatory demyelination.

    PubMed

    Mari, Elisabeth R; Moore, Jason N; Zhang, Guang-Xian; Rostami, Abdolmohamad

    2015-08-01

    Multiple sclerosis is a complex autoimmune disease of the central nervous system that results in a disruption of the balance between pro-inflammatory and anti-inflammatory signals in the immune system. Given that central nervous system inflammation can be suppressed by various immunological tolerance mechanisms, immune tolerance has become a focus of research in the attempt to induce long-lasting immune suppression of pathogenic T cells. Mechanisms underlying this tolerance induction include induction of regulatory T cell populations, anergy and the induction of tolerogenic antigen-presenting cells. The intravenous administration of encephalitogenic peptides has been shown to suppress experimental autoimmune encephalomyelitis and induce tolerance by promoting the generation of regulatory T cells and inducing apoptosis of pathogenic T cells. Safe and effective methods of inducing long-lasting immune tolerance are essential for the treatment of multiple sclerosis. By exploring tolerogenic mechanisms, new strategies can be devised to strengthen the regulatory, anti-inflammatory cell populations thereby weakening the pathogenic, pro-inflammatory cell populations.

  14. Epimerization in peptide thioester condensation.

    PubMed

    Teruya, Kenta; Tanaka, Takeyuki; Kawakami, Toru; Akaji, Kenichi; Aimoto, Saburo

    2012-11-01

    Peptide segment couplings are now widely utilized in protein chemical synthesis. One of the key structures for the strategy is the peptide thioester. Peptide thioester condensation, in which a C-terminal peptide thioester is selectively activated by silver ions then condensed with an amino component, is a powerful tool. But the amino acid adjacent to the thioester is at risk of epimerization. During the preparation of peptide thioesters by the Boc solid-phase method, no substantial epimerization of the C-terminal amino acid was detected. Epimerization was, however, observed during a thioester-thiol exchange reaction and segment condensation in DMSO in the presence of a base. In contrast, thioester-thiol exchange reactions in aqueous solutions gave no epimerization. The epimerization during segment condensation was significantly suppressed with a less polar solvent that is applicable to segments in thioester peptide condensation. These results were applied to a longer peptide thioester condensation. The epimer content of the coupling product of 89 residues was reduced from 27% to 6% in a condensation between segments of 45 and 44 residues for the thioester and the amino component, respectively.

  15. Vitamin D in inflammatory diseases

    PubMed Central

    Wöbke, Thea K.; Sorg, Bernd L.; Steinhilber, Dieter

    2014-01-01

    Changes in vitamin D serum levels have been associated with inflammatory diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis (MS), atherosclerosis, or asthma. Genome- and transcriptome-wide studies indicate that vitamin D signaling modulates many inflammatory responses on several levels. This includes (i) the regulation of the expression of genes which generate pro-inflammatory mediators, such as cyclooxygenases or 5-lipoxygenase, (ii) the interference with transcription factors, such as NF-κB, which regulate the expression of inflammatory genes and (iii) the activation of signaling cascades, such as MAP kinases which mediate inflammatory responses. Vitamin D targets various tissues and cell types, a number of which belong to the immune system, such as monocytes/macrophages, dendritic cells (DCs) as well as B- and T cells, leading to individual responses of each cell type. One hallmark of these specific vitamin D effects is the cell-type specific regulation of genes involved in the regulation of inflammatory processes and the interplay between vitamin D signaling and other signaling cascades involved in inflammation. An important task in the near future will be the elucidation of the regulatory mechanisms that are involved in the regulation of inflammatory responses by vitamin D on the molecular level by the use of techniques such as chromatin immunoprecipitation (ChIP), ChIP-seq, and FAIRE-seq. PMID:25071589

  16. Constrained Cyclic Peptides as Immunomodulatory Inhibitors of the CD2:CD58 Protein-Protein Interaction.

    PubMed

    Sable, Rushikesh; Durek, Thomas; Taneja, Veena; Craik, David J; Pallerla, Sandeep; Gauthier, Ted; Jois, Seetharama

    2016-08-19

    The interaction between the cell-cell adhesion proteins CD2 and CD58 plays a crucial role in lymphocyte recruitment to inflammatory sites, and inhibitors of this interaction have potential as immunomodulatory drugs in autoimmune diseases. Peptides from the CD2 adhesion domain were designed to inhibit CD2:CD58 interactions. To improve the stability of the peptides, β-sheet epitopes from the CD2 region implicated in CD58 recognition were grafted into the cyclic peptide frameworks of sunflower trypsin inhibitor and rhesus theta defensin. The designed multicyclic peptides were evaluated for their ability to modulate cell-cell interactions in three different cell adhesion assays, with one candidate, SFTI-a, showing potent activity in the nanomolar range (IC50: 51 nM). This peptide also suppresses the immune responses in T cells obtained from mice that exhibit the autoimmune disease rheumatoid arthritis. SFTI-a was resistant to thermal denaturation, as judged by circular dichroism spectroscopy and mass spectrometry, and had a half-life of ∼24 h in human serum. Binding of this peptide to CD58 was predicted by molecular docking studies and experimentally confirmed by surface plasmon resonance experiments. Our results suggest that cyclic peptides from natural sources are promising scaffolds for modulating protein-protein interactions that are typically difficult to target with small-molecule compounds.

  17. Apolipoprotein Mimetic Peptides: Mechanisms of Action as Anti-atherogenic Agents

    PubMed Central

    Osei-Hwedieh, David O.; Amar, Marcelo; Sviridov, Dmitri; Remaley, Alan T.

    2011-01-01

    Apolipoprotein mimetic peptides are short synthetic peptides that share structural, as well as biological features of native apolipoproteins. The early positive clinical trials of intravaenous preparations of apoA-I, the main protein component of high density lipoproteins (HDL), have stimulated great interest in the use of apolipoprotein mimetic peptides as possible therapeutic agents. Currently, there are a wide variety of apolipoprotein mimetic peptides at various stages of drug development. These peptides typically have been designed to either promote cholesterol efflux or act as anti-oxidants, but they usually exert other biological effects, such as anti-inflammatory and anti-thrombotic effects. Uncertainty about which of these biological properties is the most important for explaining their anti-atherogenic effect is a major unresolved question in the field. Structure-function studies relating the in vitro properties of these peptides to their ability to reduce atherosclerosis in animal models may uncover the best rationale for the design of these peptides and may lead to a better understanding of the mechanisms behind the atheroprotective effect of HDL. PMID:21172387

  18. Recent trends in the analysis of bioactive peptides in milk and dairy products.

    PubMed

    Capriotti, Anna Laura; Cavaliere, Chiara; Piovesana, Susy; Samperi, Roberto; Laganà, Aldo

    2016-04-01

    Food-derived constituents represent important sources of several classes of bioactive compounds. Among them peptides have gained great attention in the last two decades thanks to the scientific evidence of their beneficial effects on health in addition to their established nutritional value. Several functionalities for bioactive peptides have been described, including antioxidative, antihypertensive, anti-inflammatory, immunomodulatory, and antimicrobial activity. They are now considered as novel and potential dietary ingredients to promote human health, though in some cases they may also have detrimental effects on health. Bioactive peptides can be naturally occurring, produced in vitro by enzymatic hydrolysis, and formed in vivo during gastrointestinal digestion of proteins. Thus, the need to gain a better understanding of the positive health effects of food peptides has prompted the development of analytical strategies for their isolation, separation, and identification in complex food matrices. Dairy products and milk are potential sources of bioactive peptides: several of them possess extra-nutritional physiological functions that qualify them to be classified under the functional food label. In this trends article we briefly describe the state-of-the-art of peptidomics methods for the identification and discovery of bioactive peptides, also considering recent progress in their analysis and highlighting the difficulty in the analysis of short amino acid sequences and endogenous peptides.

  19. Protective effect of wheat peptides against indomethacin-induced oxidative stress in IEC-6 cells.

    PubMed

    Yin, Hong; Pan, Xingchang; Song, Zhixiu; Wang, Shaokang; Yang, Ligang; Sun, Guiju

    2014-01-29

    Recent studies have demonstrated that wheat peptides protected rats against non-steroidal anti-inflammatory drugs-induced small intestinal epithelial cells damage, but the mechanism of action is unclear. In the present study, an indomethacin-induced oxidative stress model was used to investigate the effect of wheat peptides on the nuclear factor-κB(NF-κB)-inducible nitric oxide synthase-nitric oxide signal pathway in intestinal epithelial cells-6 cells. IEC-6 cells were treated with wheat peptides (0, 125, 500 and 2000 mg/L) for 24 h, followed by 90 mg/L indomethacin for 12 h. Wheat peptides significantly attenuated the indomethacin-induced decrease in superoxide dismutase and glutathione peroxidase activity. Wheat peptides at 2000 mg/L markedly decreased the expression of the NF-κB in response to indomethacin-induced oxidative stress. This study demonstrated that the addition of wheat peptides to a culture medium significantly inhibited the indomethacin-induced release of malondialdehyde and nitrogen monoxide, and increased antioxidant enzyme activity in IEC-6 cells, thereby providing a possible explanation for the protective effect proposed for wheat peptides in the prevention of indomethacin-induced oxidative stress in small intestinal epithelial cells.

  20. Lipid Bodies in Inflammatory Cells

    PubMed Central

    Melo, Rossana C. N.; D’Avila, Heloisa; Wan, Hsiao-Ching; Bozza, Patrícia T.; Dvorak, Ann M.; Weller, Peter F.

    2011-01-01

    Lipid bodies (LBs), also known as lipid droplets, have increasingly been recognized as functionally active organelles linked to diverse biological functions and human diseases. These organelles are actively formed in vivo within cells from the immune system, such as macrophages, neutrophils, and eosinophils, in response to different inflammatory conditions and are sites for synthesis and storage of inflammatory mediators. In this review, the authors discuss structural and functional aspects of LBs and current imaging techniques to visualize these organelles in cells engaged in inflammatory processes, including infectious diseases. The dynamic morphological aspects of LBs in leukocytes as inducible, newly formable organelles, elicitable in response to stimuli that lead to cellular activation, contribute to the evolving understanding of LBs as organelles that are critical regulators of different inflammatory diseases, key markers of leukocyte activation, and attractive targets for novel anti-inflammatory therapies. PMID:21430261

  1. Multidimensional peptide separations in proteomics.

    PubMed

    Link, Andrew J

    2002-12-01

    Multidimensional peptide separation will play an increasingly important role in the drive to identify and quantitate the proteome. By increasing the peak and load capacity, multidimensional approaches increase the number and dynamic range of peptides that can be analyzed in a complex biological organism. Separation methods using different physical properties of peptides have been combined with varying degrees of success. The ultimate goal is a rapid separation strategy that can be coupled with analytical methods, such as mass spectrometry, to provide comprehensive monitoring of the changing concentration, interactions, and structures of proteins in the proteome.

  2. Peptide inhibition of p22phox and Rubicon interaction as a therapeutic strategy for septic shock.

    PubMed

    Kim, Ye-Ram; Koh, Hyun-Jung; Kim, Jae-Sung; Yun, Jin-Seung; Jang, Kiseok; Lee, Joo-Youn; Jung, Jae U; Yang, Chul-Su

    2016-09-01

    Sepsis is a clinical syndrome that complicates severe infection and is characterized by the systemic inflammatory response syndrome (SIRS), is a life threatening disease characterized by inflammation of the entire body. Upon microbial infection, p22phox-gp91phox NADPH oxidase (NOX) complexes produce reactive oxygen species (ROS) that are critical for the elimination of invading microbes. However, excess production of ROS represents a key element in the cascade of deleterious processes in sepsis. We have previously reported direct crosstalk between autophagy and phagocytosis machineries by demonstrating that the Rubicon protein interacts with p22phox upon microbial infection, facilitating phagosomal trafficking of the p22phox-gp91phox NOX complex to induce a ROS burst, inflammatory cytokine production, and thereby, potent anti-microbial activities. Here, we showed N8 peptide, an N-terminal 8-amino acid peptide derived from p22phox, was sufficient for Rubicon interaction and thus, capable of robustly blocking the Rubicon-p22phox interaction and profoundly suppressing ROS and inflammatory cytokine production. Consequently, treatment with the Tat-N8 peptide or a N8 peptide-mimetic small-molecule dramatically reduced the mortality associated with Cecal-Ligation-and-Puncture-induced polymicrobial sepsis in mice. This study demonstrates a new anti-sepsis therapeutic strategy by blocking the crosstalk between autophagy and phagocytosis innate immunity machineries, representing a potential paradigm shift for urgently needed therapeutic intervention against this life-threatening SIRS.

  3. Peptides derived from CXCL8 based on in silico analysis inhibit CXCL8 interactions with its receptor CXCR1

    NASA Astrophysics Data System (ADS)

    Jiang, Shinn-Jong; Liou, Je-Wen; Chang, Chun-Chun; Chung, Yi; Lin, Lee-Fong; Hsu, Hao-Jen

    2015-12-01

    Chemokine CXCL8 is crucial for regulation of inflammatory and immune responses via activating its cognate receptor CXCR1. In this study, molecular docking and binding free energy calculations were combined to predict the initial binding event of CXCL8 to CXCR1 for peptide drug design. The simulations reveal that in the initial binding, the N-loop of CXCL8 interacts with the N-terminus of CXCR1, which is dominated by electrostatic interactions. The derived peptides from the binding region of CXCL8 are synthesized for further confirmation. Surface plasmon resonance analyses indicate that the CXCL8 derived peptide with 14 residues is able to bind to the receptor CXCR1 derived peptide with equilibrium KD of 252 μM while the peptide encompassing a CXCL8 K15A mutation hardly binds to CXCR1 derived peptide (KD = 1553 μM). The cell experiments show that the designed peptide inhibits CXCL8-induced and LPS-activated monocytes adhesion and transmigration. However, when the peptides were mutated on two lysine residues (K15 and K20), the inhibition effects were greatly reduced indicating these two amino acids are key residues for the initial binding of CXCL8 to CXCR1. This study demonstrates that in silico prediction based functional peptide design can be effective for developing anti-inflammation drugs.

  4. Pachymodulin, a new functional formyl peptide receptor 2 peptidic ligand isolated from frog skin has Janus-like immunomodulatory capacities.

    PubMed

    Lacombe, Claire; Piesse, Christophe; Sagan, Sandrine; Combadière, Christophe; Rosenstein, Yvonne; Auvynet, Constance

    2015-02-12

    Recruitment of leukocytes is essential to fight infections or to heal injuries; however, excessive and/or prolonged responses favor the development of major inflammatory pathologies, such as cardiovascular or neurodegenerative diseases. Thus, it is of great interest to seek novel compounds that can regulate leukocyte recruitment depending on the degree of inflammation. We have isolated and characterized, by different chromatographic techniques, mass spectrometry, and Edman sequencing, a new hexapeptide (SSLSKL) from the Mexican frog Pachymedusa dacnicolor, which we named pachymodulin. In vitro, pachymodulin promotes the migration of leukocytes through the binding and activation of the human and mouse N-formyl peptide receptor 2 (huFPR2). In vivo, it exhibits opposite biological activities: under homeostatic conditions, pachymodulin induces the recruitment of leukocytes, whereas under inflammatory conditions, it inhibits this process. Therefore, pachymodulin represents an interesting template in the quest to design new immunomodulatory drugs in the therapy of immune-related diseases.

  5. Early peptidic enzymes

    NASA Astrophysics Data System (ADS)

    Brack, André; Barbier, Bernard

    Oligopeptides supposed to be essential to primitive living cells could not be obtained by a prebiotic organic chemistry working mainly at random. Selection pathways were required. Experimental evidence is given for selective condensation of amino-acids in water as well as for selective resistance to degradation. Polycationic polypeptides containing lysyl (or arginyl) and hydrophobic residues strongly accelerate the hydrolysis of oligoribonucleotides. A ionic complex is first formed and the polypeptides are particularly active when they adopt a stable conformation, β-sheet or α-helix, in the complex. Well-defined short peptides were synthesized in order to determine the critical chain-length required for chemical activity. In a contemporary cell, proteins represent about 40 % of the dry weight. They fulfil a structural role and they are particularly helpful as chemical catalysts (enzymes). They can be represented as long chains made of twenty different building blocks, the amino-acids NH2-CHR-COOH, which differ by the side-chain R. Proteins are remarkable in the sense that they use amino-acids having only one carbon atom between the -NH2 and -COOH functions. The central carbon atom has always the same spatial asymmetry (chirality) and always bears a hydrogen atom. When the side-chain R is a hydrocarbon, it is branched. When R contains a chemical function, the side functions do not participate to the peptide bond construction. The protein chain results from the condensation of amino-acids, i.e. water molecules are removed between molecules in a medium which is mainly aqueous (the cell contains 75 % of water). The protein chains adopt rigid asymmetric conformations (α-helices, β-sheet structures) which are essential for the protein functions. Proteins, even the smallest ones, are too sophisticated entities to be considered as the products of an organic chemistry working at random, without any chemical selection. The chemist has therefore to understand, with simple

  6. Chronic inflammatory demyelinating polyneuropathy.

    PubMed

    Vanasse, Michel; Rossignol, Elsa; Hadad, Elie

    2013-01-01

    Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterized clinically by a progressive symmetrical weakness evolving over a period of at least 2 months. There is increased CSF protein and conduction block, reduced nerve conduction velocities, increased distal latencies, and/or absent F wave or prolonged F wave latency in two or more nerves. Incidence is lower in children (10 times less) than in adults, and the condition presents in an acute or subacute manner with frequent relapses. It is not associated with other systemic diseases such as neoplasia, diabetes mellitus, or monoclonal gammopathies. It appears to be immune-related as a variety of humoral and cellular autoimmune mechanisms have been implicated. Treatment is based on results obtained in randomized clinical trials (RCTs) conducted in adults as such studies are lacking in the pediatric population. The evolution of CIDP is more favorable in children than in adults, with 80-100% response rates to standard treatments (steroids, intravenous immunoglobulins, and/or plasmapheresis) and excellent outcome with complete functional recovery in most patients. Cases refractory to standard therapies do exist in children, for which azathioprine, methotrexate, and mycophenolate mofetil alone or more often in association with other treatments have been used. However, safety and efficacy data are still insufficient to give specific recommendations regarding the optimal choice.

  7. Chronic inflammatory demyelinating polyneuropathy.

    PubMed

    Lewis, Richard A

    2017-10-01

    As a syndrome with typical and atypical cases, chronic inflammatory demyelinating polyneuropathy (CIDP) has been a difficult disorder to diagnose and treat. The pathophysiologic basis for CIDP has not been established, contributing to the challenges in dealing with these patients. However, as one of only a handful of treatable peripheral neuropathies, there has been a tendency to diagnose CIDP to attempt a therapeutic intervention. We are also aware that there has also been overtreatment of some patients. This combination of overdiagnosis and prolonged treatment has been a concern. This chapter will review these challenges and discuss recent findings that will lead to improved diagnosis and treatment. The factors leading to misdiagnosis of CIDP were explored in a cohort of patients referred to a neuromuscular center. On a more positive note, the identification of two disorders with antibodies directed at paranodal constituents has excited the field. Treatment options have increased and been clarified. Pulse corticosteroids have been compared with oral prednisone and with intravenous immunoglobulin. The clinical trial of subcutaneous immunoglobulin in CIDP has shown both efficacy and a very low side effect profile adding to our therapeutic options. The current review will identify recent developments that show both the challenges and the exciting growth in our ability to diagnose and treat CIDP.

  8. Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control

    PubMed Central

    Lee, Young-Sun; Jun, Hee-Sook

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone mainly secreted from intestinal L cells in response to nutrient ingestion. GLP-1 has beneficial effects for glucose homeostasis by stimulating insulin secretion from pancreatic beta-cells, delaying gastric emptying, decreasing plasma glucagon, reducing food intake, and stimulating glucose disposal. Therefore, GLP-1-based therapies such as GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4, which is a GLP-1 inactivating enzyme, have been developed for treatment of type 2 diabetes. In addition to glucose-lowering effects, emerging data suggests that GLP-1-based therapies also show anti-inflammatory effects in chronic inflammatory diseases including type 1 and 2 diabetes, atherosclerosis, neurodegenerative disorders, nonalcoholic steatohepatitis, diabetic nephropathy, asthma, and psoriasis. This review outlines the anti-inflammatory actions of GLP-1-based therapies on diseases associated with chronic inflammation in vivo and in vitro, and their molecular mechanisms of anti-inflammatory action. PMID:27110066

  9. Antinociception by neutrophil-derived opioid peptides in noninflamed tissue--role of hypertonicity and the perineurium.

    PubMed

    Rittner, H L; Hackel, D; Yamdeu, R-S; Mousa, S A; Stein, C; Schäfer, M; Brack, A

    2009-05-01

    Inflammatory pain can be controlled by intraplantar opioid injection or by secretion of endogenous opioid peptides from leukocytes in inflamed rat paws. Antinociception requires binding of opioid peptides to opioid receptors on peripheral sensory nerve terminals. In the absence of inflammation, hydrophilic opioid peptides do not penetrate the perineurial barrier and, thus, do not elicit antinociception. This study was designed to examine the conditions under which endogenous, neutrophil-derived hydrophilic opioid peptides (i.e. Met-Enkephalin and beta-endorphin) can raise nociceptive thresholds in noninflamed tissue in rats. Intraplantar injection of the chemokine CXCL2/3 (macrophage inflammatory protein-2) induced selective neutrophil recruitment without overt signs of inflammation or changes in mechanical nociceptive thresholds (paw pressure threshold). Following intraplantar injection of hypertonic saline, the perineurial barrier was permeable for hours and intraplantar injection of opioid peptides increased mechanical nociceptive thresholds. While formyl-Met-Leu-Phe (fMLP) triggered opioid peptide release from neutrophils in vitro, nociceptive thresholds were unchanged in vivo. In vitro, hypertonicity interfered with fMLP-induced p38 mitogen activated kinase (MAPK) phosphorylation and opioid peptide release from neutrophils. These inhibitory effects were fully reversible by washout. In vivo, return to normotonicity occurred within 30min while the perineurium remained permeable for hours. Under these conditions, fMLP triggered MAPK phosphorylation and induced opioid peptide-mediated increases in nociceptive thresholds in the noninflamed paw. Taken together, antinociception mediated by endogenous opioids in noninflamed tissue has two important requirements: (i) opening of the perineurial barrier for opioid peptide access and (ii) opioid peptide release from neutrophils involving p38 MAPK.

  10. N-truncation and pyroglutaminylation enhances the opsonizing capacity of Aβ-peptides and facilitates phagocytosis by macrophages and microglia.

    PubMed

    Condic, Mateja; Oberstein, Timo Jan; Herrmann, Martin; Reimann, Mareike Carola; Kornhuber, Johannes; Maler, Juan Manuel; Spitzer, Philipp

    2014-10-01

    Abnormal accumulations of amyloid-β (Aβ)-peptides are one of the pathological hallmarks of Alzheimer's disease (AD). The precursor of the Aβ-peptides, the amyloid precursor protein (APP), is also found in peripheral blood cells, but its function in these cells remains elusive. We previously observed that mononuclear phagocytes release Aβ-peptides during activation and phagocytosis, suggesting a physiologic role in inflammatory processes. Here, we show that supplementing the media with soluble N-terminally truncated Aβ(2-40) and Aβ(2-42) as well as Aβ(1-42) induced the phagocytosis of polystyrene particles (PSPs) by primary human monocytes. If the PSPs were pre-incubated with Aβ-peptides, phagocytosis was induced by all tested Aβ-peptide species. N-terminally truncated Aβ(x-42) induced the phagocytosis of PSPs significantly more effectively than did Aβ(x-40). Similarly, the phagocytosis of Escherichia coli by GM-CSF- and M-CSF-elicited macrophages as well as microglia was particularly facilitated by pre-incubation with N-terminally truncated Aβ(x-42). The proinflammatory polarization of monocytes was indicated by the reduced MSRI expression and IL-10 secretion after phagocytosis of PSPs coated with Aβ(1-42), Aβ(2-42) and Aβ(3p-42). Polarization of the macrophages by GM-CSF reduced the phagocytic activity, but it did not affect the capabilities of Aβ-peptides to opsonize prey. Taken together, Aβ-peptides support phagocytosis as soluble factors and act as opsonins. Differential effects among the Aβ-peptide variants point to distinct mechanisms of interaction among monocytes/macrophages, prey and Aβ-peptides. A proinflammatory polarization induced by the phagocytosis of Aβ-peptide coated particles may provide a model for the chronic inflammatory reaction and sustained plaque deposition in AD.

  11. Femtosecond laser-patterned nanopore arrays for surface-mediated peptide treatment

    PubMed Central

    Zachman, Angela L.; Hofmeister, Lucas H.; Costa, Lino; Boire, Timothy C.; Hwang, Yu-Shik; Hofmeister, William H.

    2013-01-01

    The major goal of this study was to create easy-to-use, reusable substrates capable of storing any peptides or bioactive molecules for a desired period of time until cells uptake them without the need for bioactive molecule or peptide-specific techniques. Nanopore arrays of uniform size and distribution were machined into fused silica substrates using femtosecond laser ablation and loaded with peptides by simple adsorption. The nanopore substrates were validated by examining the effect of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) loaded nanopores on macrophage phagocytosis and intracellular production of reactive oxygen species (ROS) with and without the pro-inflammatory lipopolysaccharide (LPS). Our results demonstrated that nanopores were generated in a uniform array fashion. Ac-SDKP peptides were stably stored in nanopores and internalized by macrophages. Significant reductions in ROS production and phagocytosis in macrophages were observed over control substrates, even in combination with LPS stimulation, indicating that loading Ac-SDKP peptides in pores significantly improved the anti-inflammatory effects. PMID:24090768

  12. Multiple MAG peptides are recognized by circulating T and B lymphocytes in polyneuropathy and multiple sclerosis.

    PubMed

    Andersson, M; Yu, M; Söderström, M; Weerth, S; Baig, S; Solders, G; Link, H

    2002-05-01

    Abnormal immune responses to myelin associated glycoprotein (MAG), a component of myelin of the central and peripheral nervous system, have been suggested to play a role in the pathogenesis of multiple sclerosis (MS) and certain types of inflammatory polyneuropathy. To identify possible immunodominant MAG peptides in neuroinflammation, we examined T and B cell responses to five selected synthetic MAG peptides and myelin proteins in 21 patients with non-inflammatory polyneuropathy, 26 patients with MS, 10 optic neuritis patients and 17 healthy subjects. Enzyme-linked immunosorbent spot-forming cell assays were adopted, allowing the detection and enumeration of individual antigen responsive T and B cells in body fluids. Patients with polyneuropathy as well as those with MS had elevated levels of T and B cells recognizing MAG and its peptides. Any of the five MAG peptides under study functioned as immunodominant T and/or B cell epitope in individual subjects. None of the MAG peptides elicited a specific disease-associated T or B cell response. The enhanced T and B cell response to myelin components like MAG may play some role in initiation and/or progression of these diseases, but they could also represent secondary responses associated with myelin damage and indicate tolerization rather than autoaggressive immunity.

  13. Mitochondrial-derived N-formyl peptides: novel links between trauma, vascular collapse and sepsis.

    PubMed

    Wenceslau, C F; McCarthy, C G; Goulopoulou, S; Szasz, T; NeSmith, E G; Webb, R C

    2013-10-01

    Sepsis is a major cause of mortality and morbidity in trauma patients despite aggressive treatment. Traumatic injury may trigger infective or non-infective systemic inflammatory response syndrome (SIRS) and sepsis. Sepsis and SIRS are accompanied by an inability to regulate the inflammatory response but the cause of this perturbation is still unknown. The major pathophysiological characteristic of sepsis is the vascular collapse (i.e., loss of control of vascular tone); however, at the cellular level the final mediator of extreme vasodilatation has yet to be identified. After trauma, cellular injury releases endogenous damage-associated molecular patterns (DAMPs) that activate the innate immune system. Mitochondrial DAMPs express at least two molecular signatures, N-formyl peptides and mitochondrial DNA that act on formyl peptide receptors (FPRs) and Toll-like receptor 9, respectively. N-Formyl peptides are potent immunocyte activators and, once released in the circulation, they induce modulation of vascular tone by cellular mechanisms that are not completely understood. We have observed that N-formyl peptides from bacterial (FMLP) and mitochondrial (FMIT) sources induce FPR-mediated vasodilatation in resistance arteries. Accordingly, we propose that tissue and cellular trauma induces the release of N-formyl peptides from mitochondria triggering inflammation and vascular collapse via activation of FPR and contributing to the development of sepsis. The proposed hypothesis provides clinically significant information linking trauma, mitochondrial N-formyl peptides and inflammation to vascular collapse and sepsis. If our hypothesis is true, it may lead to new strategies in the management of sepsis that can help clinicians effectively manage non-infectious and infectious inflammatory responses. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Marine Peptides: Bioactivities and Applications

    PubMed Central