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Design of Antimicrobial Peptides: Progress Made with Human Cathelicidin LL-37.
Wang, G, Narayana, JL, Mishra, B, Zhang, Y, Wang, F, Wang, C, Zarena, D, Lushnikova, T, Wang, X
Advances in experimental medicine and biology. 2019;:215-240
Abstract
The incorporation of the innate immune system into humans is essential for survival and health due to the rapid replication of invading microbes and the delayed action of the adaptive immune system. Antimicrobial peptides are important components of human innate immunity. Over 100 such peptides have been identified in various human tissues. Human cathelicidin LL-37 is best studied, and there has been a growing interest in designing new peptides based on LL-37. This chapter describes the alternative processing of the human cathelicidin precursor, protease digestion, and lab cutting of LL-37. Both a synthetic peptide library and structure-based design are utilized to identify the active regions. Although challenging, the determination of the 3D structure of LL-37 enabled the identification of the core antimicrobial region. The minimal region of LL-37 can be function-dependent. We discuss the design and potential applications of LL-37 into antibacterial, antibiofilm, antiviral, antifungal, immune modulating, and anticancer peptides. LL-37 has been engineered into 17BIPHE2, a stable, selective, and potent antimicrobial, antibiofilm, and anticancer peptide. Both 17BIPHE2 and SAAP-148 can eliminate the ESKAPE pathogens and show topical in vivo antibiofilm efficacy. Also discussed are other application strategies, including peptide formulation, antimicrobial implants, and peptide-inducing factors such as vitamin D and sunlight. Finally, we summarize what we learned from peptide design based on human LL-37.
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Antimicrobial Host Defence Peptides: Immunomodulatory Functions and Translational Prospects.
van der Does, AM, Hiemstra, PS, Mookherjee, N
Advances in experimental medicine and biology. 2019;:149-171
Abstract
Cationic host defence peptides (CHDPs), also known as antimicrobial peptides, exhibit a wide range of activities contributing to immune responses and resolution of infections. CHDPs are expressed across diverse species, are generally amphipathic with less than 50 amino acids in length, and differ significantly in sequence and structure. This chapter focuses on the role of these peptides in immunity. CHDPs are known to function in both innate and adaptive immune responses. These peptides exert both pro- and anti-inflammatory properties, which are likely context dependent based on cell and tissue type, concentration of the peptides, and its interaction with other factors in the microenvironment. Furthermore, the crosstalk between CHDPs and the microbiome and how this may influence mucosal immunity is a rapidly emerging field of research. Overall, the immunomodulatory functions of CHDPs play an important role in the control of infections, regulation of inflammation, and maintaining immune homeostasis. It is thus not surprising that dysregulation of expression of CHDPs is implicated in the susceptibility, pathology, and progression of various diseases. In this chapter, we summarize the immunomodulatory functions of CHDPs, its clinical relevance, and the translational opportunities that these peptides provide for the development of new therapies.
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3.
Current understanding of the gut microbiota shaping mechanisms.
Chang, CS, Kao, CY
Journal of biomedical science. 2019;(1):59
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Abstract
Increasing evidences have shown strong associations between gut microbiota and many human diseases, and understanding the dynamic crosstalks of host-microbe interaction in the gut has become necessary for the detection, prevention, or therapy of diseases. Many reports have showed that diet, nutrient, pharmacologic factors and many other stimuli play dominant roles in the modulation of gut microbial compositions. However, it is inappropriate to neglect the impact of host factors on shaping the gut microbiota. In this review, we highlighted the current findings of the host factors that could modulate the gut microbiota. Particularly the epithelium-associated factors, including the innate immune sensors, anti-microbial peptides, mucus barrier, secretory IgAs, epithelial microvilli, epithelial tight junctions, epithelium metabolism, oxygen barrier, and even the microRNAs are discussed in the context of the microbiota shaping. With these shaping factors, the gut epithelial cells could select the residing microbes and affect the microbial composition. This knowledge not only could provide the opportunities to better control many diseases, but may also be used for predicting the success of fecal microbiota transplantation clinically.
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Cooperative interaction of antimicrobial peptides with the interrelated immune pathways in plants.
Bolouri Moghaddam, MR, Vilcinskas, A, Rahnamaeian, M
Molecular plant pathology. 2016;(3):464-71
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Abstract
Plants express a diverse repertoire of functionally and structurally distinct antimicrobial peptides (AMPs) which provide innate immunity by acting directly against a wide range of pathogens. AMPs are expressed in nearly all plant organs, either constitutively or in response to microbial infections. In addition to their direct activity, they also contribute to plant immunity by modulating defence responses resulting from pathogen-associated molecular pattern/effector-triggered immunity, and also interact with other AMPs and pathways involving mitogen-activated protein kinases, reactive oxygen species, hormonal cross-talk and sugar signalling. Such links among AMPs and defence signalling pathways are poorly understood and there is no clear model for their interactions. This article provides a critical review of the empirical data to shed light on the wider role of AMPs in the robust and resource-effective defence responses of plants.
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Alternatives for antibiotics - antimicrobial peptides and phages.
Żelechowska, P, Agier, J, Kozłowska, E, Brzezińska-Błaszczyk, E
Przeglad lekarski. 2016;(5):334-9
Abstract
The constant increase in the number of bacteria resistant to antibiotics poses a substantial problem for the therapy of infectious diseases of different etiologies. The growing insensitivity of pathogens on the classical methods of treatment is associated mainly with multiple mechanisms of resistance created by bacteria. Furthermore, no proper antibiotic treatment causes the appearance of resistant strains even at the last line drugs. Therefore, there are still being sought alternatives in the treatment of difficult to eradicate pathogens. The antimicrobial peptides including cathelicidins, defensins, lysozyme, lactoferrin, histatins and bacteriocins arouse huge interest as potential therapeutics. They exhibit a broad spectrum of activity against many Gram-positive and Gram-negative bacteria, but also against fungi. Moreover, they are considered much safer than antibiotics, due to the fact that they are present in all eukaryotic organisms, in which they are an essential element of the immune system. In addition, phage therapy is also strongly recommended as alternative antibacterial approach. In this review we highlight the potential uses of antimicrobial peptides and bacteriophages in the treatment of infections of various etiologies.
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Ultraviolet radiation-induced upregulation of antimicrobial proteins in health and disease.
Felton, S, Navid, F, Schwarz, A, Schwarz, T, Gläser, R, Rhodes, LE
Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology. 2013;(1):29-36
Abstract
This article reviews recent data on the expression, regulation and activation of antimicrobial peptides (AMP) in human skin, and considers their potential protective and pro-inflammatory roles following upregulation by ultraviolet radiation (UVR). Antimicrobial peptides are small peptides that are key components of the innate immune system, originally identified by their vital role in protecting the body-environment interface from infection. However, it has now become clear that AMP have more extensive actions, including the provision of pivotal links with the adaptive immune system. Moreover, aberrant AMP expression may contribute to immuno-modulated inflammatory dermatoses including psoriasis, eczema and the photoaggravated condition lupus erythematosus. Recent work has demonstrated the direct upregulation of AMP in healthy skin by cutaneous UVR exposure. This may serve to protect the skin from risks imposed by both the biophysical barrier-compromise and the immunosuppression that are attributable to UVR exposure. Furthermore, it is observed that UVR provokes upregulation of AMP in an atypical manner in the photosensitivity disorder polymorphic light eruption. Dysregulated UVR responses of these pro-inflammatory proteins may play a role in the pathogenesis of certain immune-mediated diseases caused or aggravated by sunlight.
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[New insights in the pathogenesis and treatment of rosacea].
Palatsi, R, Kelhälä, HL, Hägg, P
Duodecim; laaketieteellinen aikakauskirja. 2012;(22):2327-35
Abstract
The production of cathelicidin, an antimicrobial peptide is strongly increased in rosacea. Cathelicidin activates innate immunity, inflammation and angiogenesis. Cutaneous proteases produce inflammatory fragments of cathelicidin. UV-B irradiation and microbial components increase vitamin D3 and TLR2 expression in keratinocytes leading to an increase of cathelicidin production. Retinoids and doxycycline inhibit inflammation, proteases, angiogenesis and TLR2 expression. A multicenter study 2010 proved that isotretinoin with a dose of 0,3 mg/kg/d for 12 weeks and doxycycline with the dose of 100 mg/d for 14 days followed with 50 mg/d were equally effective. Doxycycline 40 mg/d is also effective in milder cases.
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Induction of the human cathelicidin LL-37 as a novel treatment against bacterial infections.
van der Does, AM, Bergman, P, Agerberth, B, Lindbom, L
Journal of leukocyte biology. 2012;(4):735-42
Abstract
As traditional antibiotics gradually become inefficient, there is a high demand for development of anti-infectives with a mechanism of action that is different from existing antibiotics. Current antibiotics target the pathogen directly, thereby contributing to the selection of multidrug-resistant bacterial strains. AMPs, such as the human cathelicidin LL-37, are small cationic peptides that are part of host defense. They eliminate microbes through diverse mechanisms, thereby contributing to resolution of infections and maintenance of epithelial barrier function. The multiplicity of these mechanisms of action might be a key to restrict the development of resistant bacterial strains. The discovery of LL-37-inducing components, such as butyrate and vitamin D(3), has opened new avenues to prevent or treat infections. Butyrate and vitamin D(3) are potent inducers of LL-37 but in addition, have many other effects on host immunity. Here, we summarize current data on the effects that LL-37 and its inducers display on the innate immune response and discuss the feasibility for development of these inducers as possible drugs to prevent or treat infections.
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[Application on food preservative of antimicrobial peptides].
Zhao, H, Mu, Y, Zhao, B
Wei sheng yan jiu = Journal of hygiene research. 2009;(4):502-4
Abstract
Antimicrobial peptides are an integral component of the innate immune system, it can counteract outer membrane pathogen such as bacteria, fungi, viruses, protozoan and so on. Owing to the sterilization and innocuity, it has the potential to be crude food preservative. In this paper the uses of antibacterial peptides in the food preservative were analyzed.
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Antimicrobial peptides, innate immunity, and the normally sterile urinary tract.
Zasloff, M
Journal of the American Society of Nephrology : JASN. 2007;(11):2810-6
Abstract
Considering the anatomical location of the urethral meatus, it is surprising that urine is normally sterile. The defensive properties of uroepithelia help maintain this sterility as strategically necessary for long-term survival. Epithelia lining the urinary tract prevent adhesion of bacteria by release of Tamm-Horsfall protein, lactoferrin, lipocalin, and constitutive and inducible bactericidal antimicrobial peptides such as alpha- and beta-defensins and cathelicidin. Microbes that overwhelm these early defenses contact uroepithelia and activate an innate immune response through Toll-like receptor 4. With persistence of increasing numbers of microbes, chemokines (IL-8) and cytokines (IL-1 and TNFalpha) attract and activate large numbers of neutrophils and macrophages that damage tubulointerstitial parenchyma. The risk of serious infection in humans seems quite variable. Cathelicidin, for example, is a vitamin D-dependent gene, and vitamin D stores may influence susceptibility to urinary tract infection in selected individuals. As more knowledge accrues, vitamin D supplementation may someday be useful as adjuvant therapy in this setting.