Journal articles on the topic 'Pro-rich, defensins, antimicrobial peptides'
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1
Meraj, Sanam, Arshvir Singh Dhari, Emerson Mohr, Carl Lowenberger, and Gerhard Gries. "Characterization of New Defensin Antimicrobial Peptides and Their Expression in Bed Bugs in Response to Bacterial Ingestion and Injection." International Journal of Molecular Sciences 23, no. 19 (September 29, 2022): 11505. http://dx.doi.org/10.3390/ijms231911505.
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Common bed bugs, Cimex lectularius, can carry, but do not transmit, pathogens to the vertebrate hosts on which they feed. Some components of the innate immune system of bed bugs, such as antimicrobial peptides (AMPs), eliminate the pathogens. Here, we determined the molecular characteristics, structural properties, and phylogenetic relatedness of two new defensins (CL-defensin1 (XP_024085718.1), CL-defensin2 (XP_014240919.1)), and two new defensin isoforms (CL-defensin3a (XP_014240918.1), CL-defensin3b (XP_024083729.1)). The complete amino acid sequences of CL-defensin1, CL-defensin2, CL-defensin3a, and CL-defensin3b are strongly conserved, with only minor differences in their signal and pro-peptide regions. We used a combination of comparative transcriptomics and real-time quantitative PCR to evaluate the expression of these defensins in the midguts and the rest of the body of insects that had been injected with bacteria or had ingested blood containing the Gram-positive (Gr+) bacterium Bacillus subtilis and the Gram-negative (Gr–) bacterium Escherichia coli. We demonstrate, for the first time, sex-specific and immunization mode-specific upregulation of bed bug defensins in response to injection or ingestion of Gr+ or Gr– bacteria. Understanding the components, such as these defensins, of the bed bugs’ innate immune systems in response to pathogens may help unravel why bed bugs do not transmit pathogens to vertebrates.
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Adyns, Lowie, Paul Proost, and Sofie Struyf. "Role of Defensins in Tumor Biology." International Journal of Molecular Sciences 24, no. 6 (March 9, 2023): 5268. http://dx.doi.org/10.3390/ijms24065268.
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Defensins have long been considered as merely antimicrobial peptides. Throughout the years, more immune-related functions have been discovered for both the α-defensin and β-defensin subfamily. This review provides insights into the role of defensins in tumor immunity. Since defensins are present and differentially expressed in certain cancer types, researchers started to unravel their role in the tumor microenvironment. The human neutrophil peptides have been demonstrated to be directly oncolytic by permealizing the cell membrane. Further, defensins can inflict DNA damage and induce apoptosis of tumor cells. In the tumor microenvironment, defensins can act as chemoattractants for subsets of immune cells, such as T cells, immature dendritic cells, monocytes and mast cells. Additionally, by activating the targeted leukocytes, defensins generate pro-inflammatory signals. Moreover, immuno-adjuvant effects have been reported in a variety of models. Therefore, the action of defensins reaches beyond their direct antimicrobial effect, i.e., the lysis of microbes invading the mucosal surfaces. By causing an increase in pro-inflammatory signaling events, cell lysis (generating antigens) and attraction and activation of antigen presenting cells, defensins could have a relevant role in activating the adaptive immune system and generating anti-tumor immunity, and could thus contribute to the success of immune therapy.
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Sathoff, Andrew E., Siva Velivelli, Dilip M. Shah, and Deborah A. Samac. "Plant Defensin Peptides have Antifungal and Antibacterial Activity Against Human and Plant Pathogens." Phytopathology® 109, no. 3 (March 2019): 402–8. http://dx.doi.org/10.1094/phyto-09-18-0331-r.
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Plant defensins are small, cysteine-rich antimicrobial peptides. These peptides have previously been shown to primarily inhibit the growth of fungal plant pathogens. Plant defensins have a γ-core motif, defined as GXCX3-9C, which is required for their antifungal activity. To evaluate plant defensins as a potential control for a problematic agricultural disease (alfalfa crown rot), short, chemically synthesized peptides containing γ-core motif sequences were screened for activity against numerous crown rot pathogens. These peptides showed both antifungal and, surprisingly, antibacterial activity. Core motif peptides from Medicago truncatula defensins (MtDef4 and MtDef5) displayed high activity against both plant and human bacterial pathogens in vitro. Full-length defensins had higher antimicrobial activity compared with the peptides containing their predictive γ-core motifs. These results show the future promise for controlling a wide array of economically important fungal and bacterial plant pathogens through the transgenic expression of a plant defensin. They also suggest that plant defensins may be an untapped reservoir for development of therapeutic compounds for combating human and animal pathogens.
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Barroso, Carolina, Pedro Carvalho, José F. M. Gonçalves, Pedro N. S. Rodrigues, and João V. Neves. "Antimicrobial Peptides: Identification of Two Beta-Defensins in a Teleost Fish, the European Sea Bass (Dicentrarchus labrax)." Pharmaceuticals 14, no. 6 (June 14, 2021): 566. http://dx.doi.org/10.3390/ph14060566.
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Beta-defensins consist in a group of cysteine-rich antimicrobial peptides (AMPs), widely found throughout vertebrate species, including teleost fish, with antimicrobial and immunomodulatory activities. However, although the European sea bass (Dicentrarchus labrax) is one of the most commercially important farmed fish species in the Mediterranean area, the characterization of its beta-defensins and its potential applications are still missing. In this study, we characterized two members of the beta-defensin family in this species. Phylogenetic and synteny analysis places sea bass peptides in the beta-defensin subfamilies 1 and 2, sharing similar features with the other members, including the six cysteines and the tertiary structure, that consists in three antiparallel beta-sheets, with beta-defensin 1 presenting an extra alpha-helix at the N-terminal. Further studies are necessary to uncover the functions of sea bass beta-defensins, particularly their antimicrobial and immunomodulatory properties, in order to develop novel prophylactic or therapeutic compounds to be used in aquaculture production.
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Xiao, Li-Qing, Ai-Hua Liu, and Yong-Lian Zhang. "An Effective Method for Raising Antisera Against β-defensins: Double-copy Protein Expression of mBin1b in E. coli." Acta Biochimica et Biophysica Sinica 36, no. 8 (August 1, 2004): 571–76. http://dx.doi.org/10.1093/abbs/36.8.571.
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Abstract Bin1b is a rat epididymis specific β-defensin which may have fertility related functions in addition to its antimicrobial activity. β-defensins are cysteine-rich cationic antimicrobial peptides that have their important implications in innate and adaptive immunity. Though considerable numbers of new β-defensins have been discovered, few corresponding antibodies have been reported. The small peptide with special structure and antimicrobial nature of β-defensins make them very difficult to express in prokaryotic system. Here we adopted a double-copy protein expression scheme based on which not only the mBin1b protein was successfully expressed but also the immunity of the antigen was enhanced. The validity of the antisera was verified by using Western blotting and immunohistochemical analyses. It will be a useful tool for deeply investigating the roles of Bin1b and also provide a simple but effective method in raising antisera against other members of the β-defensin gene family.
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Bezhuk, Yu A., O. I. Мartovlos (Hodovana), I. I. Horban, and A. V. Tsimar. "The Role of Defensins in Non-Specific Protection of the Macroorganism from Infectious Agents in Inflammatory Diseases of the Mouth and Oropharynx (Literature Review)." Ukraïnsʹkij žurnal medicini, bìologìï ta sportu 7, no. 3 (July 2, 2022): 7–13. http://dx.doi.org/10.26693/jmbs07.03.007.
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The purpose of the study was to analyze literature sources containing information about defensins, cysteine-rich cationic amphipathic peptides produced by circulating white blood cells and tissue cells. This review describes the antimicrobial, antiviral, anti-inflammatory and immunomodulatory properties of defensins, as well as their molecular and cellular interactions. These substances, which are present on the epithelium and body fluids, are active against bacteria, fungi and viruses, as well as produced by immune and epithelial cells. These natural antimicrobial cationic peptides play an important role in innate and adaptive immunity. Defensins are divided into alpha and beta families. Alpha-defensins (α-defensins) are found in neutrophils, macrophages and Paneth cells in the intestine. Beta-defensins (β-defensins) are secreted by most leukocytes and epithelial cells. Extensive antimicrobial activity and multifaceted immunomodulatory functions of defensins confirm their role in innate immunity as the main protective component of the human body against bacterial, viral and fungal infections. Thus, they are key effector molecules in protecting the organism from infection due to their broad-spectrum antimicrobial activity. Their common antimicrobial function is the formation of destructive pores in the membranes of pathogens, including enveloped viruses. Antiviral activity includes the direct effect of defensin on viral envelopes, glycoproteins and capsids. Binding and modulation of host cell surface receptors and disruption of intracellular signaling by defensins may also inhibit virus replication. These peptides block infection with enveloped and non-enveloped viruses by aggregating particles, blocking receptor binding, inhibiting virus penetration or depletion of particles, inhibiting stem cell signaling, or viral gene expression. In addition, defensins may function as chemokines to enhance and alter adaptive immune responses by exhibiting an indirect antiviral mechanism. Conclusion. However, sources of scientific information have shown that defensins attract immune cells and modulate adaptive immune responses. It has also been shown that defensins can both induce inflammation and suppress inflammatory responses by acting on certain cells through various mechanisms. Due to this, they can be used as one of the markers in the development of inflammatory diseases of the mouth and oropharynx. The main drugs that activate the production of defensins are probiotics, vitamin D and leukotriene B4. This expands the possibility of their use as a new class of non-toxic antimicrobials and immunomodulators
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El-Shehawi, Ahmed, Saad Al-Otaibi, and Ehab Azab. "Defens in gene expression in some plant sources of Taif." Genetika 48, no. 1 (2016): 9–24. http://dx.doi.org/10.2298/gensr1601009e.
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Plant defensins are promising future strategy as antimicrobial agents; however the number of characterized plant defensins is very low. We isolated and studied the expression of plant defensins in six plants from Taif region. Using RT-PCR and two pairs of common as well as three pairs of specific primers, the defensin gene expression was analyzed. Plants showed differences in defensin gene expression in floral buds and leaves, though floral buds represented higher gene expression. The amino acid sequence of the six isolated cDNA sequences showed high similarity with other defensin accessions from the nucleotide database, especially in the cysteine rich motif. Phylogenetic analysis revealed that the isolated sequences share the common features of plant defensins, especially the 8 conserved cysteines. The results of this study help to detect some valuable Saudi plant sources for the development of natural peptides as a replacement for chemical antibiotics.
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Yount, N. Y., M. S. Wang, J. Yuan, N. Banaiee, A. J. Ouellette, and M. E. Selsted. "Rat neutrophil defensins. Precursor structures and expression during neutrophilic myelopoiesis." Journal of Immunology 155, no. 9 (November 1, 1995): 4476–84. http://dx.doi.org/10.4049/jimmunol.155.9.4476.
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Abstract Defensins constitute a family of 3- to 4-kDa antimicrobial peptides that are stored in the cytoplasmic granules of neutrophils, some macrophages, and intestinal Paneth cells. We have assessed defensin gene expression during myeloid differentiation by first characterizing cDNAs for each of the four known rat neutrophil defensins (RatNP 1-4). The cDNA sequences revealed that the peptides are synthesized as 87-94 amino acid precursors, each containing signal, pro-, and mature peptide segments. RatNP-3 and -4 mRNAs, but not those for RatNP-1 and -2 or other myeloid defensins, contained unique polypurine tracts located close to the termination codon in the 3' untranslated region. By using cDNA probes and/or riboprobes, we evaluated defensin transcript levels in a variety of tissues and in the full spectrum of neutrophil precursors. By in situ hybridization, defensin mRNAs were localized to neutrophil precursors in the bone marrow, with the highest mRNA levels occurring in promyelocytes and somewhat lower signals occurring in myeloblasts and myelocytes. Defensin mRNAs were not detectable in bands or mature neutrophils, nor at significant levels in tissues other than bone marrow. The accumulation of defensin protein in bone marrow cells was assessed by immunohistochemical staining with anti-RatNP-1 Ab. RatNP 1-4 mRNAs and protein levels were then correlated for each stage of neutrophilic differentiation to reveal the maturational profile of myeloid defensin gene expression in the rat.
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Sakamoto, Noriho, Hiroshi Mukae, Takeshi Fujii, Hiroshi Ishii, Sumako Yoshioka, Tomoyuki Kakugawa, Kanako Sugiyama, et al. "Differential effects of α- and β-defensin on cytokine production by cultured human bronchial epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 288, no. 3 (March 2005): L508—L513. http://dx.doi.org/10.1152/ajplung.00076.2004.
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Defensins are cysteine-rich cationic antimicrobial peptides that play an important role in innate immunity and are known to contribute to the regulation of host adaptive immunity. In addition to direct antimicrobial activities, it has been recently reported that α-defensins, mainly present in neutrophils in the lung, have a cytotoxic effect and induce IL-8 production from airway epithelial cells. Although β-defensins are expressed in epithelial cells in various tissues, including lung, there are no reports of their effects on cytokine synthesis in airway epithelial cells. The aim of the present study was to determine the effects of both α- and β-defensins on the cytokine production, transcription factor binding activity, and cytotoxicity in primary cultured human bronchial epithelial cells (HBECs). We used human neutrophil peptide-1 (HNP-1; α-defensin) and human β-defensin-2 (HBD-2) to stimulate HBECs. The results showed that treatment of HBECs with HNP-1, but not HBD-2, increased IL-8 and IL-1β mRNA expression in a dose-dependent manner and also enhanced IL-8 protein secretion and NF-κB DNA binding activity. The 24-h treatments with >20 μg/ml of HNP-1 or >50 μg/ml of HBD-2 were cytotoxic to HBECs. These results suggest that α- and β-defensins have different effects on cytokine synthesis by airway epithelial cells, and we speculate that they play different roles in inflammatory lung diseases.
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Moyer, Tessa B., Amanda M. Brechbill, and Leslie M. Hicks. "Mass Spectrometric Identification of Antimicrobial Peptides from Medicinal Seeds." Molecules 26, no. 23 (December 1, 2021): 7304. http://dx.doi.org/10.3390/molecules26237304.
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Traditional medicinal plants contain a variety of bioactive natural products including cysteine-rich (Cys-rich) antimicrobial peptides (AMPs). Cys-rich AMPs are often crosslinked by multiple disulfide bonds which increase their resistance to chemical and enzymatic degradation. However, this class of molecules is relatively underexplored. Herein, in silico analysis predicted 80–100 Cys-rich AMPs per species from three edible traditional medicinal plants: Linum usitatissimum (flax), Trifolium pratense (red clover), and Sesamum indicum (sesame). Bottom-up proteomic analysis of seed peptide extracts revealed direct evidence for the translation of 3–10 Cys-rich AMPs per species, including lipid transfer proteins, defensins, α-hairpinins, and snakins. Negative activity revealed by antibacterial screening highlights the importance of employing a multi-pronged approach for AMP discovery. Further, this study demonstrates that flax, red clover, and sesame are promising sources for further AMP discovery and characterization.
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Brancaccio, Mariarita, Cristina Mennitti, Mariella Calvanese, Alessandro Gentile, Roberta Musto, Giulia Gaudiello, Giulia Scamardella, et al. "Diagnostic and Therapeutic Potential for HNP-1, HBD-1 and HBD-4 in Pregnant Women with COVID-19." International Journal of Molecular Sciences 23, no. 7 (March 22, 2022): 3450. http://dx.doi.org/10.3390/ijms23073450.
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Pregnancy is characterized by significant immunological changes and a cytokine profile, as well as vitamin deficiencies that can cause problems for the correct development of a fetus. Defensins are small antimicrobial peptides that are part of the innate immune system and are involved in several biological activities. Following that, this study aims to compare the levels of various cytokines and to investigate the role of defensins between pregnant women with confirmed COVID-19 infection and pregnant women without any defined risk factor. TNF-α, TGF-β, IL-2 and IL-10, β-defensins, have been evaluated by gene expression in our population. At the same time, by ELISA assay IL-6, IL-8, defensin alpha 1, defensin beta 1 and defensin beta 4 have been measured. The data obtained show that mothers affected by COVID-19 have an increase in pro-inflammatory factors (TNF-α, TGF-β, IL-2, IL-6, IL-8) compared to controls; this increase could generate a sort of “protection of the fetus” from virus attacks. Contemporarily, we have an increase in the anti-inflammatory cytokine IL-10 and an increase in AMPs, which highlights how the mother’s body is responding to the viral attack. These results allow us to hypothesize a mechanism of “trafficking” of antimicrobial peptides from the mother to the fetus that would help the fetus to protect itself from the infection in progress.
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Bevins, Charles L. "Events at the Host-Microbial Interface of the Gastrointestinal Tract V. Paneth cell α-defensins in intestinal host defense." American Journal of Physiology-Gastrointestinal and Liver Physiology 289, no. 2 (August 2005): G173—G176. http://dx.doi.org/10.1152/ajpgi.00079.2005.
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Host defense of the small intestine is mediated, in part, by antimicrobial peptides, including α-defensins. In the small intestine, Paneth cells, specialized secretory epithelial cells located at the base of the crypt invaginations lining the intestinal wall, produce α-defensins. The α-defensins are cysteine-rich cationic peptides with antibiotic activity against a wide range of bacteria and other microbes. Studies of transgenic and knockout mice have supported a pivotal role of Paneth cell α-defensins in protection from bacterial pathogens. New data suggest that deficient expression of Paneth cell α-defensins may contribute to the pathophysiology of Crohn's disease, a chronic inflammatory bowel disease.
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Ouellette, Andre J. "IV. Paneth cell antimicrobial peptides and the biology of the mucosal barrier." American Journal of Physiology-Gastrointestinal and Liver Physiology 277, no. 2 (August 1, 1999): G257—G261. http://dx.doi.org/10.1152/ajpgi.1999.277.2.g257.
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The hypothesis that epithelial cells release preformed antibiotic peptides as components of mucosal innate immunity has gained experimental support in recent years. In the mammalian small intestine, Paneth cells secrete granules that are rich in α-defensins and additional antimicrobial peptides into the lumen of the crypt. The α-defensins are homologues of peptides that function as mediators of nonoxidative microbial cell killing in phagocytic leukocytes, and they are potent microbicidal agents in in vitro assays. Because certain mouse α-defensins stimulate cultured epithelial cells to secrete chloride ion, those peptides appear to be capable of interacting directly with the apical membranes of neighboring cells and perhaps influencing crypt physiology. In instances of crypt disruption or induced Paneth cell deficiency, crypt intermediate cells appear to compensate by accumulating and secreting Paneth cell antimicrobial peptides. Challenges for the future will be to understand the mechanisms of this epithelial plasticity and to show that Paneth cells contribute directly to innate immunity in the crypt microenvironment.
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Mitta, G., F. Vandenbulcke, T. Noel, B. Romestand, J. C. Beauvillain, M. Salzet, and P. Roch. "Differential distribution and defence involvement of antimicrobial peptides in mussel." Journal of Cell Science 113, no. 15 (August 1, 2000): 2759–69. http://dx.doi.org/10.1242/jcs.113.15.2759.
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In previous papers, we characterised 3 types of 4-kDa, cysteine-rich, cationic antimicrobial peptides: MGDs (for Mytilus galloprovincialis defensins), mytilins and myticins, which are abundant in the mussel hemocytes. In the present work, we revealed a differential distribution of the cells expressing the different genes. In addition, using confocal and electron microscopy, we confirmed that defensins and mytilins were partially located in different sub-types of circulating hemocytes although the peptides can be located in the same cell, and even in the same granule. We also demonstrated that mytilins exert their microbicidal effect within the cells through the process of phagosome-mytilin granule fusion leading to the co-location of ingested bacteria and mytilins.
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Oguiura, Nancy, Leonardo Sanches, Priscila V. Duarte, Marcos A. Sulca-López, and Maria Terêsa Machini. "Past, Present, and Future of Naturally Occurring Antimicrobials Related to Snake Venoms." Animals 13, no. 4 (February 19, 2023): 744. http://dx.doi.org/10.3390/ani13040744.
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This review focuses on proteins and peptides with antimicrobial activity because these biopolymers can be useful in the fight against infectious diseases and to overcome the critical problem of microbial resistance to antibiotics. In fact, snakes show the highest diversification among reptiles, surviving in various environments; their innate immunity is similar to mammals and the response of their plasma to bacteria and fungi has been explored mainly in ecological studies. Snake venoms are a rich source of components that have a variety of biological functions. Among them are proteins like lectins, metalloproteinases, serine proteinases, L-amino acid oxidases, phospholipases type A2, cysteine-rich secretory proteins, as well as many oligopeptides, such as waprins, cardiotoxins, cathelicidins, and β-defensins. In vitro, these biomolecules were shown to be active against bacteria, fungi, parasites, and viruses that are pathogenic to humans. Not only cathelicidins, but all other proteins and oligopeptides from snake venom have been proteolyzed to provide short antimicrobial peptides, or for use as templates for developing a variety of short unnatural sequences based on their structures. In addition to organizing and discussing an expressive amount of information, this review also describes new β-defensin sequences of Sistrurus miliarius that can lead to novel peptide-based antimicrobial agents, using a multidisciplinary approach that includes sequence phylogeny.
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Taylor, Karen, Bryan McCullough, David J. Clarke, Ross J. Langley, Tali Pechenick, Adrian Hill, Dominic J. Campopiano, Perdita E. Barran, Julia R. Dorin, and John R. W. Govan. "Covalent Dimer Species of β-Defensin Defr1 Display Potent Antimicrobial Activity against Multidrug-Resistant Bacterial Pathogens." Antimicrobial Agents and Chemotherapy 51, no. 5 (March 12, 2007): 1719–24. http://dx.doi.org/10.1128/aac.01531-06.
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ABSTRACT Beta defensins comprise a family of cationic, cysteine-rich antimicrobial peptides, predominantly expressed at epithelial surfaces. Previously we identified a unique five-cysteine defensin-related peptide (Defr1) that, when synthesized, is a mixture of dimeric isoforms and exhibits potent antimicrobial activity against Escherichia coli and Pseudomonas aeruginosa. Here we report that Defr1 displays antimicrobial activity against an extended panel of multidrug-resistant nosocomial pathogens for which antimicrobial treatment is limited or nonexistent. Defr1 fractions were collected by high-pressure liquid chromatography and analyzed by gel electrophoresis and mass spectrometry. Antimicrobial activity was initially investigated with the type strain Pseudomonas aeruginosa PAO1. All fractions tested displayed equivalent, potent antimicrobial activity levels comparable with that of the unfractionated Defr1. However, use of an oxidized, monomeric six-cysteine analogue (Defr1 Y5C), or of reduced Defr1, gave diminished antimicrobial activity. These results suggest that the covalent dimer structure of Defr1 is crucial to antimicrobial activity; this hypothesis was confirmed by investigation of a synthetic one-cysteine variant (Defr1-1cys). This gave an activity profile similar to that of synthetic Defr1 but only in an oxidized, dimeric form. Thus, we have shown that covalent, dimeric molecules based on the Defr1 β-defensin sequence demonstrate antimicrobial activity even in the absence of the canonical cysteine motif.
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Dang, Xiangli, and Guangshun Wang. "Spotlight on the Selected New Antimicrobial Innate Immune Peptides Discovered During 2015-2019." Current Topics in Medicinal Chemistry 20, no. 32 (December 3, 2020): 2984–98. http://dx.doi.org/10.2174/1568026620666201022143625.
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Background: Antibiotic resistance is a global issue and new anti-microbials are required. Introduction: Anti-microbial peptides are important players of host innate immune systems that prevent infections. Due to their ability to eliminate drug-resistant pathogens, AMPs are promising candidates for developing the next generation of anti-microbials. Methods: The anti-microbial peptide database provides a useful tool for searching, predicting, and designing new AMPs. In the period from 2015-2019, ~500 new natural peptides have been registered. Results: This article highlights a select set of new AMP members with interesting properties. Teixobactin is a cell wall inhibiting peptide antibiotic, while darobactin inhibits a chaperone and translocator for outer membrane proteins. Remarkably, cOB1, a sex pheromone from commensal enterococci, restricts the growth of multidrug-resistant Enterococcus faecalis in the gut at a picomolar concentration. A novel proline-rich AMP has been found in a plant Brassica napus. A shrimp peptide MjPen-II comprises three different sequence domains: serine-rich, proline-rich, and cysteine-rich regions. Surprisingly, an amphibian peptide urumin specifically inhibits H1 hemagglutinin-bearing influenza A virus. Defensins are abundant and typically consist of three pairs of intramolecular disulfide bonds. However, rat rattusin dimerizes via forming five pairs of intermolecular disulfide bonds. While human LL-37 can be induced by vitamin D, vitamin A induces the expression of resistin-like molecule alpha (RELMα) in mice. The isolation and characterization of an alternative human cathelicidin peptide, TLN-58, substantiates the concept of one gene multiple peptides. The involvement of a fly AMP nemuri in sleep induction may promote the research on the relationship between sleep and infection control. Conclusion: The functional roles of AMPs continue to grow and the general term “innate immune peptides” becomes useful. These discoveries widen our view on antimicrobial peptides and may open new opportunities for developing novel peptide therapeutics for different applications.
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Xu, Chuan, Annie Wang, Mariana Marin, William Honnen, Santhamani Ramasamy, Edith Porter, Selvakumar Subbian, et al. "Human Defensins Inhibit SARS-CoV-2 Infection by Blocking Viral Entry." Viruses 13, no. 7 (June 26, 2021): 1246. http://dx.doi.org/10.3390/v13071246.
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Innate immunity during acute infection plays a critical role in the disease severity of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), and is likely to contribute to COVID-19 disease outcomes. Defensins are highly abundant innate immune factors in neutrophils and epithelial cells, including intestinal Paneth cells, and exhibit antimicrobial and immune-modulatory activities. In this study, we investigated the effects of human α- and β-defensins and RC101, a θ-defensin analog, on SARS-CoV-2 infection. We found that human neutrophil peptides (HNPs) 1–3, human defensin (HD) 5 and RC101 exhibited potent antiviral activity against pseudotyped viruses expressing SARS-CoV-2 spike proteins. HNP4 and HD6 had weak anti-SARS-CoV-2 activity, whereas human β-defensins (HBD2, HBD5 and HBD6) had no effect. HNP1, HD5 and RC101 also inhibited infection by replication-competent SARS-CoV-2 viruses and SARS-CoV-2 variants. Pretreatment of cells with HNP1, HD5 or RC101 provided some protection against viral infection. These defensins did not have an effect when provided post-infection, indicating their effect was directed towards viral entry. Indeed, HNP1 inhibited viral fusion but not the binding of the spike receptor-binding domain to hACE2. The anti-SARS-CoV-2 effect of defensins was influenced by the structure of the peptides, as linear unstructured forms of HNP1 and HD5 lost their antiviral function. Pro-HD5, the precursor of HD5, did not block infection by SARS-CoV-2. High virus titers overcame the effect of low levels of HNP1, indicating that defensins act on the virion. HNP1, HD5 and RC101 also blocked viral infection of intestinal and lung epithelial cells. The protective effects of defensins reported here suggest that they may be useful additives to the antivirus arsenal and should be thoroughly studied.
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Fernie-King, B. A., D. J. Seilly, and P. J. Lachmann. "Inhibition of antimicrobial peptides by group A streptococci: SIC and DRS." Biochemical Society Transactions 34, no. 2 (March 20, 2006): 273–75. http://dx.doi.org/10.1042/bst0340273.
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SIC (streptococcal inhibitor of complement) is a 31 kDa protein secreted by a few highly virulent strains of GAS (group A streptococci), predominantly by the M1 strain. Initially described as an inhibitor of the membrane attack complex of complement, it has turned out to be a polyfunctional inhibitor of the innate mucosal immune response. The SIC protein sequence contains three domains: an N-terminal SRR (short repeat region), followed by three longer tandem repeats [LRR (long repeat region)] and a C-terminal PRR (proline-rich region). SIC inhibits the antibacterial activity of a wide range of antimicrobial peptides and proteins: i.e. lysozyme, SLPI (secretory leucocyte proteinase inhibitor), LL-37, hNP-1 (human neutrophil peptide-1) and the human β-defensins 1, 2 and 3. Analysis of the functional properties of recombinant domains of SIC shows that binding and inhibition of lysozyme and human β-defensin-3 require the SRR+LRR, as does binding to SLPI. Complement inhibition is confined to the SRR. M12 GAS secrete a protein ‘distantly related to SIC’ (DRS). DRS contains a C-terminal PRR which is significantly similar to that of SIC, but it has no central LRR and the N-terminal SRR is very different. DRS inhibits human β-defensin-3, but has no effect on lysozyme, SLPI or complement.
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Buonocore, Francesco, Anna Maria Fausto, Giulia Della Pelle, Tomislav Roncevic, Marco Gerdol, and Simona Picchietti. "Attacins: A Promising Class of Insect Antimicrobial Peptides." Antibiotics 10, no. 2 (February 20, 2021): 212. http://dx.doi.org/10.3390/antibiotics10020212.
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Insects produce a large repertoire of antimicrobial peptides (AMPs) as the first line of defense against bacteria, viruses, fungi or parasites. These peptides are produced from a large precursor that contains a signal domain, which is cleaved in vivo to produce the mature protein with antimicrobial activity. At present, AMPs from insects include several families which can be classified as cecropins, ponericins, defensins, lebocins, drosocin, Metchnikowin, gloverins, diptericins and attacins according to their structure and/or function. This short review is focused on attacins, a class of glycine-rich peptides/proteins that have been first discovered in the cecropia moth (Hyalophora cecropia). They are a rather heterogeneous group of immunity-related proteins that exhibit an antimicrobial effect mainly against Gram-negative bacteria. Here, we discuss different attacin and attacin-like AMPs that have been discovered so far and analyze their structure and phylogeny. Special focus is given to the physiological importance and mechanism of action of attacins against microbial pathogens together with their potential pharmacological applications, emphasizing their roles as antimicrobials.
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Patil, Amar, Austin L. Hughes, and Guolong Zhang. "Rapid evolution and diversification of mammalian α-defensins as revealed by comparative analysis of rodent and primate genes." Physiological Genomics 20, no. 1 (December 15, 2004): 1–11. http://dx.doi.org/10.1152/physiolgenomics.00150.2004.
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Mammalian α-defensins constitute a family of cysteine-rich, cationic antimicrobial peptides produced by phagocytes and intestinal Paneth cells, playing an important role in innate host defense. Following comprehensive computational searches, here we report the discovery of complete repertoires of the α-defensin gene family in the human, chimpanzee, rat, and mouse with new genes identified in each species. The human genome was found to encode a cluster of 10 distinct α-defensin genes and pseudogenes expanding 132 kb continuously on chromosome 8p23. Such α-defensin loci are also conserved in the syntenic chromosomal regions of chimpanzee, rat, and mouse. Phylogenetic analyses showed formation of two distinct clusters with primate α-defensins forming one cluster and rodent enteric α-defensins forming the other cluster. Species-specific clustering of genes is evident in nonprimate species but not in the primates. Phylogenetically distinct subsets of α-defensins also exist in each species, with most subsets containing multiple members. In addition, natural selection appears to have acted to diversify the functionally active mature defensin region but not signal or prosegment sequences. We concluded that mammalian α-defensin genes may have evolved from two separate ancestors originated from β-defensins. The current repertoires of the α-defensin gene family in each species are primarily a result of repeated gene duplication and positive diversifying selection after divergence of mammalian species from each other, except for the primate genes, which were evolved prior to the separation of the primate species. We argue that the presence of multiple, divergent subsets of α-defensins in each species may help animals to better cope with different microbial challenges in the ecological niches which they inhabit.
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Houyvet, Baptiste, Yolande Bouchon-Navaro, Claude Bouchon, Erwan Corre, and Céline Zatylny-Gaudin. "Marine Transcriptomics Analysis for the Identification of New Antimicrobial Peptides." Marine Drugs 19, no. 9 (August 28, 2021): 490. http://dx.doi.org/10.3390/md19090490.
Full textAbstract:
Antimicrobial peptides (AMPs) participate in the immune system to avoid infection, are present in all living organisms and can be used as drugs. Fish express numerous AMP families including defensins, cathelicidins, liver-expressed antimicrobial peptides (LEAPs), histone-derived peptides, and piscidins (a fish-specific AMP family). The present study demonstrates for the first time the occurrence of several AMPs in lionfish (Pterois volitans). Using the lionfish transcriptome, we identified four transcript sequences encoding cysteine-rich AMPs and two new transcripts encoding piscidin-like peptides. These AMPs are described for the first time in a species of the Scorpaenidae family. A functional approach on new pteroicidins was carried out to determine antimicrobial sequences and potential uses, with a view to using some of these AMPs for human health or in aquaculture.
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Li, Hui, Siva L. S. Velivelli, and Dilip M. Shah. "Antifungal Potency and Modes of Action of a Novel Olive Tree Defensin Against Closely Related Ascomycete Fungal Pathogens." Molecular Plant-Microbe Interactions® 32, no. 12 (December 2019): 1649–64. http://dx.doi.org/10.1094/mpmi-08-19-0224-r.
Full textAbstract:
Antimicrobial peptides play a pivotal role in the innate immunity of plants. Defensins are cysteine-rich antifungal peptides with multiple modes of action. A novel Oleaceae-specific defensin gene family has been discovered in the genome sequences of wild and cultivated species of a perennial olive tree, Olea europaea. OefDef1.1, a member of this defensin family, potently inhibits the in-vitro growth of ascomycete fungal pathogens Botrytis cinerea and three Fusarium spp. OefDef1.1 rapidly permeabilizes the plasma membrane of the conidial and germling cells of B. cinerea. Interestingly, it induces reactive oxygen species and translocates to the cytoplasm only in the germlings but not in the conidia. In medium containing a high concentration of Na1+, antifungal activity of OefDef1.1 is significantly reduced. Surprisingly, a chimeric OefDef1.1 peptide containing the γ-core motif of a Medicago truncatula defensin, MtDef4, displays Na1+-tolerant antifungal activity. In a phospholipid-protein overlay assay, the chimeric peptide exhibits stronger binding to its phosphoinositide partners than OefDef1.1 and is also more potent in inhibiting gray mold disease on the surface of Nicotiana benthamiana and lettuce leaves than OefDef1.1. Significant differences are observed among the four ascomycete pathogens in their responses to OefDef1.1 in growth medium with or without the elevated concentration of Na1+. The varied responses of closely related ascomycete pathogens to this defensin have implications for engineering disease resistance in plants.
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Landon, Céline, Yanyu Zhu, Mainak Mustafi, Jean-Baptiste Madinier, Dominique Lelièvre, Vincent Aucagne, Agnes F. Delmas, and James C. Weisshaar. "Real-Time Fluorescence Microscopy on Living E. coli Sheds New Light on the Antibacterial Effects of the King Penguin β-Defensin AvBD103b." International Journal of Molecular Sciences 23, no. 4 (February 12, 2022): 2057. http://dx.doi.org/10.3390/ijms23042057.
Full textAbstract:
(1) Antimicrobial peptides (AMPs) are a promising alternative to conventional antibiotics. Among AMPs, the disulfide-rich β-defensin AvBD103b, whose antibacterial activities are not inhibited by salts contrary to most other β-defensins, is particularly appealing. Information about the mechanisms of action is mandatory for the development and approval of new drugs. However, data for non-membrane-disruptive AMPs such as β-defensins are scarce, thus they still remain poorly understood. (2) We used single-cell fluorescence imaging to monitor the effects of a β-defensin (namely AvBD103b) in real time, on living E. coli, and at the physiological concentration of salts. (3) We obtained key parameters to dissect the mechanism of action. The cascade of events, inferred from our precise timing of membrane permeabilization effects, associated with the timing of bacterial growth arrest, differs significantly from the other antimicrobial compounds that we previously studied in the same physiological conditions. Moreover, the AvBD103b mechanism does not involve significant stereo-selective interaction with any chiral partner, at any step of the process. (4) The results are consistent with the suggestion that after penetrating the outer membrane and the cytoplasmic membrane, AvBD103b interacts non-specifically with a variety of polyanionic targets, leading indirectly to cell death.
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Negahdaripour, Manica, Mohammad Reza Rahbar, Zahra Mosalanejad, and Ahmad Gholami. "Theta-Defensins to Counter COVID-19 as Furin Inhibitors: In Silico Efficiency Prediction and Novel Compound Design." Computational and Mathematical Methods in Medicine 2022 (February 9, 2022): 1–15. http://dx.doi.org/10.1155/2022/9735626.
Full textAbstract:
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was characterized as a pandemic by the World Health Organization (WHO) in Dec. 2019. SARS-CoV-2 binds to the cell membrane through spike proteins on its surface and infects the cell. Furin, a host-cell enzyme, possesses a binding site for the spike protein. Thus, molecules that block furin could potentially be a therapeutic solution. Defensins are antimicrobial peptides that can hypothetically inhibit furin because of their arginine-rich structure. Theta-defensins, a subclass of defensins, have attracted attention as drug candidates due to their small size, unique structure, and involvement in several defense mechanisms. Theta-defensins could be a potential treatment for COVID-19 through furin inhibition and an anti-inflammatory mechanism. Note that inflammatory events are a significant and deadly condition that could happen at the later stages of COVID-19 infection. Here, the potential of theta-defensins against SARS-CoV-2 infection was investigated through in silico approaches. Based on docking analysis results, theta-defensins can function as furin inhibitors. Additionally, a novel candidate peptide against COVID-19 with optimal properties regarding antigenicity, stability, electrostatic potential, and binding strength was proposed. Further in vitro/in vivo investigations could verify the efficiency of the designed novel peptide.
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Wertz, Philip W., and Sarah de Szalay. "Innate Antimicrobial Defense of Skin and Oral Mucosa." Antibiotics 9, no. 4 (April 3, 2020): 159. http://dx.doi.org/10.3390/antibiotics9040159.
Full textAbstract:
This special issue intends to review and update our understanding of the antimicrobial defense mechanisms of the skin and oral cavity. These two environments are quite different in terms of water, pH, and nutrient availability, but have some common antimicrobial factors. The skin surface supports the growth of a limited range of microorganisms but provides a hostile environment for others. The growth of most microorganisms is prevented or limited by the low pH, scarcity of some nutrients such as phosphorus and the presence of antimicrobial peptides, including defensins and cathelicidins, and antimicrobial lipids, including certain fatty acids and long-chain bases. On the other hand, the oral cavity is a warm, moist, nutrient rich environment which supports the growth of diverse microflora. Saliva coating the oral soft and hard surfaces determines which microorganisms can adhere to these surfaces. Some salivary proteins bind to bacteria and prevent their attachment to surfaces. Other salivary peptides, including defensins, cathelicidins, and histatins are antimicrobial. Antimicrobial salivary proteins include lysozyme, lactoferrin, and lactoperoxidase. There are also antimicrobial fatty acids derived from salivary triglycerides and long-chain bases derived from oral epithelial sphingolipids. The various antimicrobial factors determine the microbiomes of the skin surface and the oral cavity. Alterations of these factors can result in colonization by opportunistic pathogens, and this may lead to infection. Neutrophils and lymphocytes in the connective tissue of skin and mucosa also contribute to innate immunity.
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Vogel, Hans J., David J. Schibli, Weiguo Jing, Elke M. Lohmeier-Vogel, Raquel F. Epand, and Richard M. Epand. "Towards a structure-function analysis of bovine lactoferricin and related tryptophan- and arginine-containing peptides." Biochemistry and Cell Biology 80, no. 1 (February 1, 2002): 49–63. http://dx.doi.org/10.1139/o01-213.
Full textAbstract:
The iron-binding protein lactoferrin is a multifunctional protein that has antibacterial, antifungal, antiviral, antitumour, anti-inflammatory, and immunoregulatory properties. All of these additional properties appear to be related to its highly basic N-terminal region. This part of the protein can be released in the stomach by pepsin cleavage at acid pH. The 25-residue antimicrobial peptide that is released is called lactoferricin. In this work, we review our knowledge about the structure of the peptide and attempt to relate this to its many functions. Microcalorimetry and fluorescence spectroscopy data regarding the interaction of the peptide with model membranes show that binding to net negatively charged bacterial and cancer cell membranes is preferred over neutral eukaryotic membranes. Binding of the peptide destabilizes the regular membrane bilayer structure. Residues that are of particular importance for the activity of lactoferricin are tryptophan and arginine. These two amino acids are also prevalent in "penetratins", which are regions of proteins or synthetic peptides that can spontaneously cross membranes and in short hexapeptide antimicrobial peptides derived through combinatorial chemistry. While the antimicrobial, antifungal, antitumour, and antiviral properties of lactoferricin can be related to the Trp/Arg-rich portion of the peptide, we suggest that the anti-inflammatory and immunomodulating properties are more related to a positively charged region of the molecule, which, like the alpha- and beta-defensins, may act as a chemokine. Few small peptides are involved in as wide a range of host defense functions as bovine and human lactoferricin.Key words: lactoferricin, penetratin, tryptophan, arginine, membrane perturbation, fluorescence spectroscopy, NMR spectroscopy, microcalorimetry.
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Kiatsurayanon, Chanisa, Ge Peng, and François Niyonsaba. "Opposing Roles of Antimicrobial Peptides in Skin Cancers." Current Pharmaceutical Design 28, no. 3 (January 2022): 248–58. http://dx.doi.org/10.2174/1381612827666211021163318.
Full textAbstract:
: Antimicrobial peptides (AMPs), also known as host defense peptides, are ubiquitous naturally occurring molecules secreted by various cell types of the body. In the skin, AMPs serve as a first-line innate immune defense against exogenous microorganisms, and they orchestrate adaptive immune responses to exert several immunomodulatory functions. Emerging evidence indicates that AMPs not only contribute to certain inflammatory skin diseases but also play a role in skin tumor carcinogenesis. Available data support the hypothesis that AMPs possess both pro-tumor and anti-neoplastic properties. Although inconsistent observations reported by multiple studies make it challenging to summarize the precise roles of AMPs in cancer, the differential expression of AMPs in skin cancers, such as the increased expression of human beta-defensins in squamous cell carcinoma and the ability of cathelicidin LL-37 to induce malignant melanoma cell invasion, implies they have procancer activities. On the other hand, the observation that certain AMPs show cytotoxic activity against cancer cells of the colon and kidney suggests their inherent antitumor properties. In this review, we describe the roles and mechanisms of AMPs in skin cancer development. We believe that further research is needed to elucidate the impact of these AMPs in skin cancer biology and to explore their potential roles as diagnostic/prognostic biomarkers and as novel therapeutic targets.
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Ishaq, Nida, Muhammad Bilal, and Hafiz Iqbal. "Medicinal Potentialities of Plant Defensins: A Review with Applied Perspectives." Medicines 6, no. 1 (February 19, 2019): 29. http://dx.doi.org/10.3390/medicines6010029.
Full textAbstract:
Plant-based secondary metabolites with medicinal potentialities such as defensins are small, cysteine-rich peptides that represent an imperative aspect of the inherent defense system. Plant defensins possess broad-spectrum biological activities, e.g., bactericidal and insecticidal actions, as well as antifungal, antiviral, and anticancer activities. The unique structural and functional attributes provide a nonspecific and versatile means of combating a variety of microbial pathogens, i.e., fungi, bacteria, protozoa, and enveloped viruses. Some defensins in plants involved in other functions include the development of metal tolerance and the role in sexual reproduction, while most of the defensins make up the innate immune system of the plants. Defensins are structurally and functionally linked and have been characterized in various eukaryotic microorganisms, mammals, plants, gulls, teleost species of fish, mollusks, insect pests, arachnidan, and crustaceans. This defense mechanism has been improved biotechnologically as it helps to protect plants from fungal attacks in genetically modified organisms (GMO). Herein, we review plant defensins as secondary metabolites with medicinal potentialities. The first half of the review elaborates the origin, structural variations, and mechanism of actions of plant defensins. In the second part, the role of defensins in plant defense, stress response, and reproduction are discussed with suitable examples. Lastly, the biological applications of plant defensins as potential antimicrobial and anticancer agents are also deliberated. In summary, plant defensins may open a new prospect in medicine, human health, and agriculture.
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Segarra, Sergi, Tanesha Naiken, Julien Garnier, Valérie Hamon, Nathalie Coussay, and François-Xavier Bernard. "Enhanced In Vitro Expression of Filaggrin and Antimicrobial Peptides Following Application of Glycosaminoglycans and a Sphingomyelin-Rich Lipid Extract." Veterinary Sciences 9, no. 7 (June 27, 2022): 323. http://dx.doi.org/10.3390/vetsci9070323.
Full textAbstract:
Filaggrin is an epidermal protein involved in skin barrier formation and hydration, whose expression is altered in canine atopic dermatitis (CAD). CAD patients also present an abnormal immune response with an altered expression of antimicrobial peptides (AMPs), such as β-defensins and cathelicidins. Sphingolipids and glycosaminoglycans (GAGs) have been reported to improve the skin barrier in several animal species, including dogs. Our objective was to evaluate the in vitro effects of a sphingomyelin-rich lipid extract (LE), a hyaluronic acid-rich GAG matrix, and their combination, on the expression of filaggrin and human β-defensin 2 (hBD-2). Filaggrin expression was quantified in a reconstructed human epidermis (RHE), and hBD-2 in normal human epidermal keratinocyte (NHEK) cultures. LE and GAGs were tested at 0.02 mg/mL, with or without adding a cytokine mix. A significant increase in mean hBD-2, compared to the control (99 pg/mL) was achieved with LE (138 pg/mL) and LE+GAGs (165 pg/mL). Filaggrin increased with GAGs (202% ± 83) and LE (193% ± 44) vs. the stimulated control, but this difference was statistically significant (p < 0.05) only with LE+GAGs (210% ± 39). In conclusion, the tested GAGs and LE enhance filaggrin and AMP expression in vitro, which might benefit CAD patients if applied in vivo.
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Odintsova, T. I., M. P. Slezina, and E. A. Istomina. "Plant thionins: structure, biological functions and potential use in biotechnology." Vavilov Journal of Genetics and Breeding 22, no. 6 (September 27, 2018): 667–75. http://dx.doi.org/10.18699/vj18.409.
Full textAbstract:
Antimicrobial peptides (AMPs) are important components of defense system in both plants and animals. They represent an ancient mechanism of innate immunity providing rapid first line of defense against pathogens. Plant AMPs are classified into several families: thionins, defensins, nonspecific lipid-transfer proteins, hevein- and knottin-type peptides, hairpinins and macrocyclic peptides (cyclotides). The review focuses on the thionin family. Thionins comprise a plant-specific AMP family that consists of short (~5 kDA) cysteine-rich peptides containing 6 or 8 cysteine residues with antimicrobial and toxic properties. Based on similarity in amino acid sequences and the arrangement of disulphide bonds, five structural classes of thionins are discriminated. The three-dimensional structures of a number of thionins were determined. The amphipathic thionin molecule resembles the Greek letter Г, in which the long arm is formed by two antiparallel α-helices, while the short one, by two parallel β-strands. The residues responsible for the antimicrobial activity of thionins were identified. Thionins are synthesized as precursor proteins consisting of a signal peptide, the mature peptide region and the C-terminal prodomain. Thionins protect plants from pathogenic bacteria and fungi acting directly on the membranes of microorganisms at micromolar concentrations, although their precise mode of action remains unclear. In addition to plant pathogens, thionins inhibit growth of a number of human pathogens and opportunistic microorganisms, such as Candida spp., Saccharomyces cerevisiae, Fusarium solani, Staphylococcus aureus and Escherichia coli. Thionins are toxic to different types of cells including mammalian cancer cell lines. Transgenic plants expressing thionin genes display enhanced resistance to pathogens. A wide range of biological activities makes thionins promising candidates for practical application in agriculture and medicine.
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DeMmon, Diego M., Ottavia Benedicenti, Elisa Casadei, and Irene Salinas. "The diversity of beta defensins in lungfish (Dipnoi)." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 59.16. http://dx.doi.org/10.4049/jimmunol.208.supp.59.16.
Full textAbstract:
Abstract Mucosal surfaces are the first line of defense against pathogens. At these surfaces, mucus containing innate and adaptive immune molecules is constantly secreted to protect the animal host. African lungfish are the extant relatives to all tetrapods and have a dual mode of living, swimming in freshwater during the wet seasons and aestivating during the dry seasons. During terrestrialization, African lungfish produce large amounts of mucus that form a dry cocoon to prevent water loss. We recently reported that the lungfish cocoon acts as a bacterial trapping structure and it is rich in antimicrobial peptides (AMPs), specifically beta defensins (BD). As many AMPs, BDs are small amphipathic molecules and mainly cationic. The goal of this study is to provide a full characterization of BD genes from transcriptomes and genomes of different lungfish species. Using the canonical six cysteine motif from vertebrate BD molecules, we searched for all BD genes Protopterus dolloi transcriptomes, the genomes of P. annectens and Australian lungfish (a non-aestivating lungfish, Neoceratodus forsteri). BLASTs searches identified 9 BD genes in P. dolloi transcriptomes with predicted highly cationic characteristics except for BD-7. Sequence alignment and phylogenetic trees indicate that three P. dolloi BD genes may be an intermediate form of AMP between beta and alpha defensins. Genomic analyses indicate that P. annectens BD genes contain 3 exons and 2 introns similar to all defensin genes. Future studies will determine the tissue distribution and antimicrobial function of Protopterus spp. BD molecules and determine their potential application as alternatives to antibiotics. Supported by National Science Foundation Integral Organismal Systems (IOS) award # 1938816
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Parmley, RT, CS Gilbert, and LA Boxer. "Abnormal peroxidase-positive granules in “specific granule” deficiency." Blood 73, no. 3 (February 15, 1989): 838–44. http://dx.doi.org/10.1182/blood.v73.3.838.838.
Full textAbstract:
Abstract “Specific granule” deficiency (SGD) has been previously associated with lactoferrin deficiency. The antimicrobial peptides termed defensins, comprising 30% of normal primary granule proteins, have also been shown to be markedly deficient in SGD. The present study was undertaken to correlate these findings with ultrastructural morphometric analysis and peroxidase cytochemistry. Peroxidase-positive, rim-stained, large, defensin-rich dense granules, previously described as a subpopulation of azurophil or primary granules in normal neutrophils, were markedly decreased in a patient with SGD. Morphometric studies of peroxidase- positive granules indicated an average peroxidase-positive granule area (all profiles) in the patient of 0.019 +/- 0.017 micron 2 (mean +/- SD, n = 941) compared to control values from normal neutrophils of two volunteers of 0.049 +/- 0.033 micron 2 (n = 896) and 0.050 +/- 0.039 micron 2 (n = 873) (P less than 0.001 between patient and control samples). Granule histograms showed a single peak of small peroxidase- positive granules, whereas control samples contained more prominent subpopulations of larger peroxidase-positive granules. The total number of peroxidase-positive granules per 100 micron 2 of cytoplasm in the patient was 255 +/- 124 (mean +/- SD, n = 15 cell profiles), which was similar to control values of 266 +/- 63 and 212 +/- 109. Thus, the defensin deficiency in SGD is associated with a decrease in size rather than number of peroxidase-positive granules; suggesting that defensins contribute to normal peroxidase-positive granule size and that SGD is a more global granule deficiency than originally thought.(ABSTRACT TRUNCATED AT 250 WORDS)
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Parmley, RT, CS Gilbert, and LA Boxer. "Abnormal peroxidase-positive granules in “specific granule” deficiency." Blood 73, no. 3 (February 15, 1989): 838–44. http://dx.doi.org/10.1182/blood.v73.3.838.bloodjournal733838.
Full textAbstract:
“Specific granule” deficiency (SGD) has been previously associated with lactoferrin deficiency. The antimicrobial peptides termed defensins, comprising 30% of normal primary granule proteins, have also been shown to be markedly deficient in SGD. The present study was undertaken to correlate these findings with ultrastructural morphometric analysis and peroxidase cytochemistry. Peroxidase-positive, rim-stained, large, defensin-rich dense granules, previously described as a subpopulation of azurophil or primary granules in normal neutrophils, were markedly decreased in a patient with SGD. Morphometric studies of peroxidase- positive granules indicated an average peroxidase-positive granule area (all profiles) in the patient of 0.019 +/- 0.017 micron 2 (mean +/- SD, n = 941) compared to control values from normal neutrophils of two volunteers of 0.049 +/- 0.033 micron 2 (n = 896) and 0.050 +/- 0.039 micron 2 (n = 873) (P less than 0.001 between patient and control samples). Granule histograms showed a single peak of small peroxidase- positive granules, whereas control samples contained more prominent subpopulations of larger peroxidase-positive granules. The total number of peroxidase-positive granules per 100 micron 2 of cytoplasm in the patient was 255 +/- 124 (mean +/- SD, n = 15 cell profiles), which was similar to control values of 266 +/- 63 and 212 +/- 109. Thus, the defensin deficiency in SGD is associated with a decrease in size rather than number of peroxidase-positive granules; suggesting that defensins contribute to normal peroxidase-positive granule size and that SGD is a more global granule deficiency than originally thought.(ABSTRACT TRUNCATED AT 250 WORDS)
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Santos-Silva, Carlos André dos, Luisa Zupin, Marx Oliveira-Lima, Lívia Maria Batista Vilela, João Pacifico Bezerra-Neto, José Ribamar Ferreira-Neto, José Diogo Cavalcanti Ferreira, et al. "Plant Antimicrobial Peptides: State of the Art, In Silico Prediction and Perspectives in the Omics Era." Bioinformatics and Biology Insights 14 (January 2020): 117793222095273. http://dx.doi.org/10.1177/1177932220952739.
Full textAbstract:
Even before the perception or interaction with pathogens, plants rely on constitutively guardian molecules, often specific to tissue or stage, with further expression after contact with the pathogen. These guardians include small molecules as antimicrobial peptides (AMPs), generally cysteine-rich, functioning to prevent pathogen establishment. Some of these AMPs are shared among eukaryotes (eg, defensins and cyclotides), others are plant specific (eg, snakins), while some are specific to certain plant families (such as heveins). When compared with other organisms, plants tend to present a higher amount of AMP isoforms due to gene duplications or polyploidy, an occurrence possibly also associated with the sessile habit of plants, which prevents them from evading biotic and environmental stresses. Therefore, plants arise as a rich resource for new AMPs. As these molecules are difficult to retrieve from databases using simple sequence alignments, a description of their characteristics and in silico (bioinformatics) approaches used to retrieve them is provided, considering resources and databases available. The possibilities and applications based on tools versus database approaches are considerable and have been so far underestimated.
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Pero, Brancaccio, Laneri, Biasi, Lombardo, and Scudiero. "A Novel View of Human Helicobacter pylori Infections: Interplay between Microbiota and Beta-Defensins." Biomolecules 9, no. 6 (June 18, 2019): 237. http://dx.doi.org/10.3390/biom9060237.
Full textAbstract:
The gut microbiota is significantly involved in the preservation of the immune system of the host, protecting it against the pathogenic bacteria of the stomach. The correlation between gut microbiota and the host response supports human gastric homeostasis. Gut microbes may be shifted in Helicobacter pylori (Hp)-infected individuals to advance gastric inflammation and distinguished diseases. Particularly interesting is the establishment of cooperation between gut microbiota and antimicrobial peptides (AMPs) of the host in the gastrointestinal tract. AMPs have great importance in the innate immune reactions to Hp and participate in conservative co-evolution with an intricate microbiome. β-Defensins, a class of short, cationic, arginine-rich proteins belonging to the AMP group, are produced by epithelial and immunological cells. Their expression is enhanced during Hp infection. In this review, we discuss the impact of the gut microbiome on the host response, with particular regard to β-defensins in Hp-associated infections. In microbial infections, mostly in precancerous lesions induced by Hp infection, these modifications could lead to different outcomes.
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Jalodia, Richa, Jingjing Meng, Madhulika Sharma, Sundaram Ramakrishnan, and Sabita Roy. "Morphine dysregulates Paneth cell antimicrobial peptide secretion in a TLR2 dependent manner." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 49.22. http://dx.doi.org/10.4049/jimmunol.200.supp.49.22.
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Abstract Opioids are the gold standard for moderate to severe pain management. Although, the co-morbidities associated with chronic morphine use on systemic immune function has been well demonstrated by our lab and others its effect on mucosal immunity and gut homeostasis are less well defined. We have recently demonstrated that morphine treatment disrupts intestinal epithelial barrier function and suppresses systemic immune function leading to altered gut microbial dysbiosis and inflammation. We have also shown in vivo that morphine can alter the immune response by APCs leading to reduced host immune response. However, the cross talk between the gut microbiome and host intestinal epithelium and immune cells has never been explored. Paneth cells are one of the main secretory component of intestinal epithelial layer that secrete antimicrobial peptides which maintains gut homeostasis between pathogenic and commensal microbes. They also secrete pro-inflammatory cytokines which regulate the functions of mucosal immune cells. In both a murine in vivo model and in an in vitro organoid epithelial culture model we show a direct effect of morphine on paneth cells. Intraperitonial morphine treatment significantly increases the transcription level of antimicrobial peptides, a-defensins, lysozyme, Regg as well as intestinal pro-inflammatory cytokine IL1b, IL6 and TNFa levels in C57/B6 mice model. These results are also corroborated in in vitro organoid cultures. Surprisingly, these effects were completely abolished in a Toll-like receptor-2 (TLR2) knock out mice suggesting that the effect is mediated through TLR2. The role of TLR 2 and the cell type that mediates morphine’s effects will be further investigated using TLR2 floxed mice.
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Ramírez Thomé, Saira, Beatriz Ávila Curiel, María T. Hernández Huerta, and Carlos Solórzano Mata. "β-defensinas como posibles indicadores de la actividad inflamatoria en la enfermedad periodontal." Investigación Clínica 63, no. 4 (November 11, 2022): 414–34. http://dx.doi.org/10.54817/ic.v63n4a08.
Full textAbstract:
Periodontal disease (gingivitis and periodontitis) is an inflam-matory process caused by the activity of pathogenic bacteria and their products on the gingival sulcus, with the consequent activation of the immune response. Saliva and crevicular fluid contain a wide variety of enzymes and antimicrobial factors that are in contact with the supragingival and subgingival region, in-cluding β-defensins (hBDs). hHBDs are non-glycosylated, cysteine-rich cationic peptides produced by epithelial cells with antimicrobial and immunoregulatory effects, thus contributing to maintaining homeostasis in periodontal tissues. The changes in the microbiota and the immune response from a healthy peri-odontium to gingivitis and, finally, to periodontitis are complex. Their sever-ity depends on a dynamic balance between bacteria associated with plaque, genetic and environmental factors. Recent advances have made it possible to understand the implication of hBDs in the detection, diagnosis, and therapy of periodontal disease and the relationship between periodontitis and other inflammatory conditions. This review aims to describe the effect of hBDs on the immune response and its use as a possible marker of the inflammatory activity of the periodontal disease.
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Yavari, Mina, and Changiz Ahmadizadeh. "Effect of the Cellular Extract of Co-cultured Lactobacillus Casei on BAX and Human β-Defensin 2 Genes Expression in HT29 Cells." Quarterly of the Horizon of Medical Sciences 26, no. 4 (October 1, 2020): 364–81. http://dx.doi.org/10.32598/hms.26.4.3277.1.
Full textAbstract:
Aims: Defensins are cysteine-rich antimicrobial cationic peptides and BAX is a proapoptotic gene that can cause cell death. This study aimed to investigate the effect of cellular extract of co-cultured Lactobacillus casei on the expression of BAX and human β-defensin 2 (hBD-2) genes in HT29 cells. Methods & Materials: This experimental study was conducted in the Research Center for Pharmaceutical Nanotechnology of Tabriz University of Medical Sciences in 2017. The HT29 cell line was obtained from the Pasteur Institute of Iran, and cells were assessed using Microculture Tetrazolium Test (MTT) after culturing. DNA was extracted from the treated cells, and then the DNA ladder assay was carried out. After preparing cDNA, the expression levels of BAX and hBD-2 genes in the HT29 cell line were measured using a real-time Polymerase Chain Reaction (PCR) method. Findings: The results of the MTT assay indicated that Lactobacillus casei inhibited the proliferation of HT29 cells and induced apoptosis in these cells. Results of DAPI staining and DNA ladder assay obtained from treating HT29 cells by Lactobacillus casei showed qualitative changes in cell apoptosis. Moreover, realtime PCR results indicated that Lactobacillus casei bacteria significantly increased the expression of the hBD-2 gene in HT29 colon cancer cells within 12-24 hours (P= 0.023), while BAX gene expression showed no significant change in the first 24 hours (P= 0.37). Conclusion: The extract of Lactobacillus casei can be used to stimulate cancer cells to produce β-defensins, inhibit pathogens, prevent the stimulation of cellular signaling, and fight antibiotic-resistant bacteria.
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Jones, F., G. Doherty, and E. McNamee. "P071 Crohn’s Disease is associated with elevated levels of the pro-inflammatory CXCR3 ligands (CXCL9, 10 and 11) with an associated reduction in Paneth cell derived antimicrobial peptides in ex-vivo ileal biopsies." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S174—S175. http://dx.doi.org/10.1093/ecco-jcc/jjab076.200.
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Abstract Background Despite an expanding array of treatment options, a significant proportion of patients with Crohn’s Disease (CD) fail to respond to currently available therapies, underpinning the importance of biological insights into disease pathogenesis. The pro-inflammatory chemokines CXCL9,10 and 11 bind to the CXCR3 receptor, highly expressed on effector T-cells. Mouse models of chronic ileitis have shown that CXCR3+ effector T cells drive the loss of paneth cells that play an important role in innate immunity and mucosal barrier function. In the TNFΔΔARE mouse ileitis-model, small molecule inhibition of the CXCR3 receptor reverses paneth cell loss and restores antimicrobial peptide levels. The aims of this study were to evaluate the role of chemokines that bind to CXCR3+ effector T-cells in adult patients with ileal CD compared to healthy controls and to assess the impact of these pro-inflammatory chemokines on paneth cell derived anti-microbial peptides. Methods, 13 CD patients and 16 healthy controls attending for routine endoscopic evaluation were prospectively recruited at St.Vincent’s University Hospital, Dublin and ileal biopsies were collected in media. RNA was isolated from homogenised ileal biopsies (Quiagen kit), DNAse treated using DNAse I (Invitrogen) and reverse transcribed using M-MLV reverse transcriptase (Promega). Target cDNAs were quantified using an Applied BiosystemsTM QuantStudioTM 7 Flex Real-Time PCR System. Results We identified an increase in the relative mRNA expression of CXCR3 associated chemokines, with significantly higher levels of CXCL9, CXCL10 and CXCL11 in ileal CD patients compared to healthy controls. This coincides with a reduction in paneth cell-derived antimicrobial peptides with significantly lower levels of alpha defensins (DEFA5, DEFA6) and lysozyme in CD patients compared to healthy controls. Conclusion This study supports data from animal models and provides a hypothesis for the loss of paneth cells in patients with ileal CD. The reduction in paneth cell derived anti-microbial peptides may help to explain the altered microbiome and provide an explanation for the loss of mucosal barrier integrity in Inflammatory Bowel Disease (IBD). A greater understanding of the role of chemokines in the development of mucosal immunity and inflammation in IBD may allow the targeting of chemokines in novel therapeutic strategies.
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Greco, Samuele, Marco Gerdol, Paolo Edomi, and Alberto Pallavicini. "Molecular Diversity of Mytilin-Like Defense Peptides in Mytilidae (Mollusca, Bivalvia)." Antibiotics 9, no. 1 (January 19, 2020): 37. http://dx.doi.org/10.3390/antibiotics9010037.
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The CS-αβ architecture is a structural scaffold shared by a high number of small, cationic, cysteine-rich defense peptides, found in nearly all the major branches of the tree of life. Although several CS-αβ peptides involved in innate immune response have been described so far in bivalve mollusks, a clear-cut definition of their molecular diversity is still lacking, leaving the evolutionary relationship among defensins, mytilins, myticins and other structurally similar antimicrobial peptides still unclear. In this study, we performed a comprehensive bioinformatic screening of the genomes and transcriptomes available for marine mussels (Mytilida), redefining the distribution of mytilin-like CS-αβ peptides, which in spite of limited primary sequence similarity maintain in all cases a well-conserved backbone, stabilized by four disulfide bonds. Variations in the size of the alpha-helix and the two antiparallel beta strand region, as well as the positioning of the cysteine residues involved in the formation of the C1–C5 disulfide bond might allow a certain degree of structural flexibility, whose functional implications remain to be investigated. The identification of mytilins in Trichomya and Perna spp. revealed that many additional CS-αβ AMPs remain to be formally described and functionally characterized in Mytilidae, and suggest that a more robust scheme should be used for the future classification of such peptides with respect with their evolutionary origin.
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Malyshev, M. E., A. K. Iordanishvili, P. A. Mushegyan, and T. G. Khabirova. "Secretory immune status of oral cavity in the patients with Сandida-associated denture stomatitis." Medical Immunology (Russia) 23, no. 3 (June 22, 2021): 577–84. http://dx.doi.org/10.15789/1563-0625-sis-2230.
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Age-related changes in the oral mucosa immunity, including decreased contents of secretory immunoglobulins and antimicrobial peptides in saliva, along with changed balance of pro- and antiinflammatory cytokines, care risks for development of purulent-inflammatory or allergic diseases of the oral cavity. For example, denture stomatitis (DS) caused by Candida albicans occurs in about 30—70% of denture users. The purpose of this study was to assess the secretory immune state of oral mucous membranes in the patients with Candida-associated denture stomatitis. We examined 42 elderly patients (61-72 years old) with one-piece acrylic dentures for at least, 6 months (15 men and 27 women). Based on clinical and microbiological studies, the patients were divided into a group with DS (n = 24) and a group without DS (n = 18). The contents of secretory immunoglobulin A (sIgA) and proinflammatory cytokines was determined, i.e., interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNFα), and anti-inflammatory cytokines, e.g., receptor antagonist of interleukin-1 (RAIL), interleukin-4 (IL-4), interleukin-10 (IL-10), as well as antimicrobial peptides (cathelicidin LL-37, lactoferrin and alphadefensins 1-3 (HNP1-3). The sIgA levels in the salivary fluid of patients with DS (0.92 (0.80-1.26) g/l) were significantly lower (p < 0.05) than in patients without stomatitis (1.71 (1.23-2,13) g/l). In the group with advanced DS, a significant increase of IL-1β levels in saliva was observed, along with simultaneous decrease of IL-8 concentrations, compared to the other group, without differences in TNFα and IL-6 concentrations. Increased contents of IL-10 in saliva was also noted. It was shown that the concentrations of cathelicidin LL-37 in saliva of the DS patients was increased two-fold, whereas the contents of neutrophil-derived alpha-defensins (HNP 1-3) was decreased. Conclusions: The development of inflammation in denture stomatitis caused by usage of removable acrylic dentures associated with Candida albicans infection is characterized by functional insufficiency of the secretory immunity of the oral mucosa associated with decreased amounts of secretory immunoglobulin A and antimicrobial peptides of neutrophilic origin. Low levels of alpha-defensins may suggest a decrease in the functional activity of neutrophils in the elderly, thus leading to higher susceptibility to fungal infection of oral cavity.
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Sass, Vera, Tanja Schneider, Miriam Wilmes, Christian Körner, Alessandro Tossi, Natalia Novikova, Olga Shamova, and Hans-Georg Sahl. "Human β-Defensin 3 Inhibits Cell Wall Biosynthesis in Staphylococci." Infection and Immunity 78, no. 6 (April 12, 2010): 2793–800. http://dx.doi.org/10.1128/iai.00688-09.
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ABSTRACT Human β-defensin 3 (hBD3) is a highly charged (+11) cationic host defense peptide, produced by epithelial cells and neutrophils. hBD3 retains antimicrobial activity against a broad range of pathogens, including multiresistant Staphylococcus aureus, even under high-salt conditions. Whereas antimicrobial host defense peptides are assumed to act by permeabilizing cell membranes, the transcriptional response pattern of hBD3-treated staphylococcal cells resembled that of vancomycin-treated cells (V. Sass, U. Pag, A. Tossi, G. Bierbaum, and H. G. Sahl, Int. J. Med. Microbiol. 298:619-633, 2008) and suggested that inhibition of cell wall biosynthesis is a major component of the killing process. hBD3-treated cells, inspected by transmission electron microscopy, showed localized protrusions of cytoplasmic contents, and analysis of the intracellular pool of nucleotide-activated cell wall precursors demonstrated accumulation of the final soluble precursor, UDP-MurNAc-pentapeptide. Accumulation is typically induced by antibiotics that inhibit membrane-bound steps of cell wall biosynthesis and also demonstrates that hBD3 does not impair the biosynthetic capacity of cells and does not cause gross leakage of small cytoplasmic compounds. In in vitro assays of individual membrane-associated cell wall biosynthesis reactions (MraY, MurG, FemX, and penicillin-binding protein 2 [PBP2]), hBD3 inhibited those enzymes which use the bactoprenol-bound cell wall building block lipid II as a substrate; quantitative analysis suggested that hBD3 may stoichiometrically bind to lipid II. We report that binding of hBD3 to defined, lipid II-rich sites of cell wall biosynthesis may lead to perturbation of the biosynthesis machinery, resulting in localized lesions in the cell wall as demonstrated by electron microscopy. The lesions may then allow for osmotic rupture of cells when defensins are tested under low-salt conditions.
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Telleria, Erich Loza, Bruno Tinoco-Nunes, Tereza Leštinová, Lívia Monteiro de Avellar, Antonio Jorge Tempone, André Nóbrega Pitaluga, Petr Volf, and Yara Maria Traub-Csekö. "Lutzomyia longipalpis Antimicrobial Peptides: Differential Expression during Development and Potential Involvement in Vector Interaction with Microbiota and Leishmania." Microorganisms 9, no. 6 (June 11, 2021): 1271. http://dx.doi.org/10.3390/microorganisms9061271.
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Antimicrobial peptides (AMPs) are produced to control bacteria, fungi, protozoa, and other infectious agents. Sand fly larvae develop and feed on a microbe-rich substrate, and the hematophagous females are exposed to additional pathogens. We focused on understanding the role of the AMPs attacin (Att), cecropin (Cec), and four defensins (Def1, Def2, Def3, and Def4) in Lutzomyia longipalpis, the main vector of visceral leishmaniasis in the Americas. Larvae and adults were collected under different feeding regimens, in addition to females artificially infected by Leishmania infantum. AMPs’ gene expression was assessed by qPCR, and gene function of Att and Def2 was investigated by gene silencing. The gene knockdown effect on bacteria and parasite abundance was evaluated by qPCR, and parasite development was verified by light microscopy. We demonstrate that L. longipalpis larvae and adults trigger AMPs expression during feeding, which corresponds to an abundant presence of bacteria. Att and Def2 expression were significantly increased in Leishmania-infected females, while Att suppression favored bacteria growth. In conclusion, L. longipalpis AMPs’ expression is tuned in response to bacteria and parasites but does not seem to interfere with the Leishmania cycle.
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Klein, Britta, Sudhanshu Bhushan, Stefan Günther, Ralf Middendorff, Kate L. Loveland, Mark P. Hedger, and Andreas Meinhardt. "Differential tissue-specific damage caused by bacterial epididymo-orchitis in the mouse." Molecular Human Reproduction 26, no. 4 (February 3, 2020): 215–27. http://dx.doi.org/10.1093/molehr/gaaa011.
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Abstract Ascending bacterial urinary tract infections can cause epididymo-orchitis. In the cauda epididymidis, this frequently leads to persistent tissue damage. Less coherent data is available concerning the functional consequences of epididymo-orchitis on testis and caput epididymidis. This in vivo study addresses the functional and spatial differences in responsiveness of murine epididymis and testis to infection with uropathogenic Escherichia coli (UPEC). Whole transcriptome analysis (WTA) was performed on testis, caput, corpus and cauda epididymidis of adult C57BL/6 J wildtype mice. Following UPEC-induced epididymo-orchitis in these mice, epididymal and testicular tissue damage was evaluated histologically and semi-quantitatively at 10 days and 31 days post-inoculation. Expression of inflammatory markers and candidate antimicrobial genes were analysed by RT-qPCR. WTA revealed distinct differences in gene signatures between caput and cauda epididymidis, particularly amonst immunity-related genes. Cellular and molecular signs of testicular inflammation and disruption of spermatogenesis were noticed at day 10, but recovery was observed by day 31. In contrast to the cauda, the caput epididymidis did not reveal any signs of gross morphological damage or presence of pro-inflammatory processes despite confirmed infection. In contrast to beta-defensins, known UPEC-associated antimicrobial peptides (AMP), like Lcn2, Camp and Lypd8, were inherently highly expressed or upregulated in the caput following infection, potentially allowing an early luminal protection from UPEC. At the time points investigated, the caput epididymidis was protected from any obvious infection/inflammation-derived tissue damage. Studies addressing earlier time-points will conclude whether in the caput epididymidis a pro-inflammatory response is indeed not essential for effective protection from UPEC.
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Saqib, Z., G. De Palma, J. Lu, P. Bercik, and S. M. Collins. "A43 β-DEFENSINS AS MARKERS OF INTESTINAL DYSBIOSIS: THE NATURE OF CHANGES IN β-DEFENSINS IS DEPENDENT ON THE PROCESS UNDERLYING THE INDUCTION OF DYSBIOSIS." Journal of the Canadian Association of Gastroenterology 3, Supplement_1 (February 2020): 51–52. http://dx.doi.org/10.1093/jcag/gwz047.042.
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Abstract Background Dysbiosis may be defined as a change in the microbial composition or function that results in altered host function. Defensins are antimicrobial peptides, are part of innate immunity, and are important in host defense and maintaining homeostasis. Dysbiosis is a putative mechanism underlying the expression of many functional GI disorders like Irritable Bowel Syndrome (IBS) for which no biomarkers exist. Previous studies have revealed increased β-defensin (β-Def) levels in IBS patients, most likely due to changes in the microbiota. Aims We examined the hypotheses that: 1) Changes in β-Def are dependent on the manner in which dysbiosis is induced, and that 2) the direction of the change in β-Def depends on how dysbiosis was induced. Methods We used 4 models of experimentally induced dysbiosis to determine changes in fecal β-Def and to characterize the microbiota composition before and during the induction of dysbiosis. We used: 1) an antimicrobial cocktail (AC) in water; 2) a high-fat/ high-sugar diet (HFHSD); 3) a high salt diet (HSD) that we previously showed to induce a pro-inflammatory microbiota; and 4) mild restraint stress (MRS). All studies were performed in C57/BL6 mice except studies using MRS that were performed in NIH Swiss mice. In the AC or dietary studies, we employed a one-week intervention preceded by one-week baseline and recovery periods. In MRS studies, mice comparisons were made between a control and a stressed group. Stool samples were collected every 24 hours and were assayed for fecal β-Def levels analysis by an ELISA and microbial composition by 16S gene profiling. Results Exposure to AC or dietary change, but not MRS, resulted in significant decreases in fecal β-Def. Additionally, bacterial composition and diversity profiles were different in all mice except MRS mice (control vs. MRS males: p=0.414; control vs. MRS females: p=0.96). In contrast, mice exposed to the HSD revealed a significant increase in β-Def during treatment compared to baseline in both males (p=0.025) and females (p= 0.0019). The AC mice showed the largest changes and significant correlations between changes in β-Def levels and bacterial diversity (males: p=0.013, r=0.6; females: p=0.007, r=0.6) and richness (males: p=0.0008, r=0.70; females: p=0.003, r=0.62). However, no significant correlations were found between specific bacteria and β-Def levels in the HFHSD group. Conclusions We conclude that directional changes in fecal β-Def levels are dependent on the manner in which dysbiosis is induced. The use of β-Def as a biomarker requires comparisons with baseline levels obtained during remission in order to identify dysbiosis presence in microbiota-associated chronic GI conditions like IBS. Such an approach will identify patient subgroups that may benefit from microbiota-directed therapies. Funding Agencies CIHR
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Cho, Junho, Stephen K. Costa, Rachel M. Wierzbicki, William F. C. Rigby, and Ambrose L. Cheung. "The extracellular loop of the membrane permease VraG interacts with GraS to sense cationic antimicrobial peptides in Staphylococcus aureus." PLOS Pathogens 17, no. 3 (March 1, 2021): e1009338. http://dx.doi.org/10.1371/journal.ppat.1009338.
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Host defense proteins (HDPs), aka defensins, are a key part of the innate immune system that functions by inserting into the bacterial membranes to form pores to kill invading and colonizing microorganisms. To ensure survival, microorganism such as S. aureus has developed survival strategies to sense and respond to HDPs. One key strategy in S. aureus is a two-component system (TCS) called GraRS coupled to an efflux pump that consists of a membrane permease VraG and an ATPase VraF, analogous to the BceRS-BceAB system of Bacillus subtilis but with distinct differences. While the 9 negatively charged amino acid extracellular loop of the membrane sensor GraS has been shown to be involved in sensing, the major question is how such a small loop can sense diverse HDPs. Mutation analysis in this study divulged that the vraG mutant phenocopied the graS mutant with respect to reduced activation of downstream effector mprF, reduction in surface positive charge and enhanced 2 hr. killing with LL-37 as compared with the parental MRSA strain JE2. In silico analysis revealed VraG contains a single 200-residue extracellular loop (EL) situated between the 7th and 8th transmembrane segments (out of 10). Remarkably, deletion of EL in VraG enhanced mprF expression, augmented surface positive charge and improved survival in LL-37 vs. parent JE2. As the EL of VraG is rich in lysine residues (16%), in contrast to a preponderance of negatively charged aspartic acid residues (3 out of 9) in the EL of GraS, we divulged the role of charge interaction by showing that K380 in the EL of VraG is an important residue that likely interacts with GraS to interfere with GraS-mediated signaling. Bacterial two-hybrid analysis also supported the interaction of EL of VraG with the EL of GraS. Collectively, we demonstrated an interesting facet of efflux pumps whereby the membrane permease disrupts HDP signaling by inhibiting GraS sensing that involves charged residues in the EL of VraG.
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Boyle, Joseph P., Rhiannon Parkhouse, and Tom P. Monie. "Insights into the molecular basis of the NOD2 signalling pathway." Open Biology 4, no. 12 (December 2014): 140178. http://dx.doi.org/10.1098/rsob.140178.
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The cytosolic pattern recognition receptor NOD2 is activated by the peptidoglycan fragment muramyl dipeptide to generate a proinflammatory immune response. Downstream effects include the secretion of cytokines such as interleukin 8, the upregulation of pro-interleukin 1β, the induction of autophagy, the production of antimicrobial peptides and defensins, and contributions to the maintenance of the composition of the intestinal microbiota. Polymorphisms in NOD2 are the cause of the inflammatory disorder Blau syndrome and act as susceptibility factors for the inflammatory bowel condition Crohn's disease. The complexity of NOD2 signalling is highlighted by the observation that over 30 cellular proteins interact with NOD2 directly and influence or regulate its functional activity. Previously, the majority of reviews on NOD2 function have focused upon the role of NOD2 in inflammatory disease or in its interaction with and response to microbes. However, the functionality of NOD2 is underpinned by its biochemical interactions. Consequently, in this review, we have taken the opportunity to address the more ‘basic’ elements of NOD2 signalling. In particular, we have focused upon the core interactions of NOD2 with protein factors that influence and modulate the signal transduction pathways involved in NOD2 signalling. Further, where information exists, such as in relation to the role of RIP2, we have drawn comparison with the closely related, but functionally discrete, pattern recognition receptor NOD1. Overall, we provide a comprehensive resource targeted at understanding the complexities of NOD2 signalling.
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Riabushko, N. O. "CHANGES IN QUANTITATIVE AND QUALITATIVE PROPERTIES OF ORAL LIQUID DURING REPLACEMENT OF DENTAL DEFECTS IN PATIENTS WITH ISCHEMIC HEART DISEASE." Ukrainian Dental Almanac, no. 4 (December 23, 2020): 64–69. http://dx.doi.org/10.31718/2409-0255.4.2020.12.
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Abstract. In recent years, the attention of scientists to the study of the unique properties of saliva and related diagnostic capabilities has increased significantly. Many data on the function and composition of oral fluid in healthy people and in various somatic pathologies.
The ducts of three pairs of large (parotid, mandibular, sublingual) and up to a thousand small salivary glands open into the oral cavity of an adult. The amount of saliva secreted per day depends on the nature of food, age and sex. But on average, an adult secretes 750-1500 ml of saliva per day.
Upon entering the oral cavity, saliva mixes with leukocytes, microorganisms and their products, exfoliated epithelium of the oral mucosa, oral detritus, gingival fluid, food debris, toothpaste, bronchial and nasal secretions.
The purpose of the study: to investigate changes in the quantitative and qualitative properties of oral fluid in the replacement of dentition defects in patients with coronary heart disease.
Object and methods of research. Sources of domestic and foreign literature.
Research results. Oral fluid is an integral liquid medium of the human body and the first biological fluid that connects the internal environment of the body with the external.
The activity of more than 100 enzymes, which differ in the origin and performance of the function, is determined in human oral fluid [6]. Changes in the activity of oral enzymes due to direct exposure to metal ions, plastics and related pathology can lead to a weakening of protective, mineralizing, digestive and other properties, which harms not only the dental system but also the human body as a whole.
It is established that due to changes in permeability in the conditions of stress pathology the dynamic balance of the main internal environment - blood is preserved. It is proved that changes in the biochemical composition of blood and saliva correlate with the severity and features of myocardial infarction.
Therefore, due to recent research in biochemistry and dentistry, laboratory methods continue to be improved and introduced into clinical practice, which allow to diagnose somatic and dental diseases by studying the parameters of oral fluid, which significantly expands diagnostic capabilities and allows more effective control of patients with combined pathology.
Thus, in recent years it has been proven that an important role in the development of coronary heart disease and vascular pathology belongs to homocysteine, which is an intermediate product of metabolic conversions of methionine to cysteine. In case of insufficient utilization, homocysteine leaves the cells in the liquid environment of the body, performing thrombogenic and pro-inflammatory effects.
One of the main indicators of the immunological state of oral fluid is cationic antimicrobial peptides, which are important components of the immune system of a wide range of organisms. They play a key role in providing the first line of defense for the microorganism against infection. NHP1-NHP3 contain only 30 amino acid residues.
Defensins show their microbial properties in micromolar conferences. Each representative of NHP has its own characteristic antimicrobial specificity of these peptides to each other.
Defensins have the ability to suppress viral infection. They are effective against DNA and RNA viruses. Defensins inhibit the replication of human immunodeficiency virus, have high activity against the herpes virus. Also, these peptides inhibit vesicular stomatitis virus, human cytomegalovirus, influenza virus, adenovirus, papillomavirus and others.
Conclusion. With secondary adentia (regardless of size and location), the volume of oral fluid decreases and its microelement composition changes. In addition, the replacement of dentition defects with different types of dentures causes metabolic disorders associated with the activation of free radical oxidation of biomolecules.
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Sukhareva, M. S., P. M. Kopeykin, M. S. Zharkova, and O. V. Shamova. "COMBINED ANTIBACTERIAL ACTION OF SALIVARY CATIONIC PROLINE-RICH PEPTIDES AND ANTIMICROBIAL PEPTIDES." Medical academic journal 19, no. 1S (December 15, 2019): 180–81. http://dx.doi.org/10.17816/maj191s1180-181.
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Saliva is an important biological fluid that reflects human’s health. Its main function is protection of the oral cavity from pathogens. Antimicrobial peptides (AMPs) of the innate immunity may play an important role in anti-infectious defense of the oral cavity, but their relative amount in saliva is low. It’s major component is Proline-rich peptides (PRPs), whose impact in antimicrobial protection remains poorly understood. We suggest that salivary PRPs may reveal their defensive functions upon interaction with other molecules, in particular with AMPs. The aim of this work is an investigation of the combined antibacterial action of salivary PRPs (fragments of Basic salivary proline-rich protein 1: P-H (37-51), IB6 (98-116), p1932) with antimicrobial peptides (histatin 5 and cathelicidin LL-37 and beta-defensin hBD3). Listed PRPs have been obtained by chemical solid-phase synthesis. The method of broth microdilutions was used to compare minimal inhibitory concentrations (MICs) of individual fractions of AMPs and their MICs in the presence of salivary peptides. It was found that in the presence of peptides IB6 (98-116) or P-H (37-51) the activity of defensin hBD3 was increased (reduction of MICs by 2 times) against Staphylococcus aureus SG511. In the presence of IB6 (98-116) or p1932 the activity of this defensin against E. coli ML35p was also improved (MICs of hBD3 was lowered by 2 times). For other combinations of the peptides, this effect was not observed. The obtained data confirm the assumption that the combined action of varied salivary peptides, including cationic Proline-rich peptides, plays an important role in anti-infectious protection of the oral cavity.