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Vitamin D was not associated with survival or cerebrospinal fluid cathelicidin levels in children with bacterial meningitis.
Savonius, O, Pelkonen, T, Roine, I, Viljakainen, H, Andersson, S, Fernandez, J, Peltola, H, Helve, O
Acta paediatrica (Oslo, Norway : 1992). 2018;(12):2131-2136
Abstract
AIM: Vitamin D deficiency impairs the immunological system and has been associated with worse outcomes of infectious diseases, but its role in bacterial meningitis remains unknown. We investigated whether serum 25-hydroxyvitamin D concentrations related to disease outcomes and to cerebrospinal fluid (CSF) cathelicidin concentrations in childhood bacterial meningitis. METHODS All consecutively enrolled patients in a clinical trial on childhood bacterial meningitis in Latin America in 1996-2003 were considered, and 142 children, with a median age of seven months who had a confirmed bacterial aetiology and frozen serum available for further analyses, were included in this study. Serum 25-hydroxyvitamin D concentrations were determined with a chemiluminescence immunoassay analyser, while CSF cathelicidin was measured by enzyme-linked immunosorbent assay. RESULTS The median serum 25-hydroxyvitamin D concentration was 96 (range 19-251) nmol/L. No relationship was found with patient survival, but children with any neurological sequelae had lower serum 25-hydroxyvitamin D levels than children without sequelae. Serum 25-hydroxyvitamin D was unrelated to cathelicidin concentrations in CSF. CONCLUSION Although serum 25-hydroxyvitamin D in children with bacterial meningitis was not associated with survival or CSF cathelicidin concentrations, its relationship with more detailed disease outcomes warrants further study.
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Impact of high-dose vitamin D3 on plasma free 25-hydroxyvitamin D concentrations and antimicrobial peptides in critically ill mechanically ventilated adults.
Han, JE, Alvarez, JA, Jones, JL, Tangpricha, V, Brown, MA, Hao, L, Brown, LAS, Martin, GS, Ziegler, TR
Nutrition (Burbank, Los Angeles County, Calif.). 2017;:102-108
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Abstract
OBJECTIVES High-dose vitamin D3 increases plasma total 25-hydroxyvitamin D [25(OH)D] in critically ill, ventilated patients; however, to our knowledge, the effect on plasma levels of free (nonprotein-bound) 25(OH)D has not been investigated in critical illness. Moreover, the relationship of free 25(OH)D and the regulation of endogenous antimicrobial peptides (AMPs) remains unknown. The aims of this study were to determine in critically ill adults with respiratory failure the effect of previous high-dose regimens of vitamin D3 on free 25(OH)D concentrations, the relationship of free 25(OH)D with circulating cathelicidin (LL-37) and human beta-defensin-2 (hBD-2), and the associations between plasma levels of free 25(OH)D and these AMPs to alveolar macrophage phagocytosis function. METHODS In a double blind, randomized controlled trial, critically ill ventilator-dependent adults (N = 30) received enteral vitamin D3 (250,000 or 500,000 IU total over 5 d) or placebo. Plasma was obtained serially for concentrations of free 25(OH)D, LL-37, hBD-2, and expression of peripheral blood mononuclear cell human cationic antimicrobial protein (hCAP18) mRNA. Total 25(OH)D and LL-37 concentrations and alveolar macrophage phagocytosis were determined in bronchoalveolar lavage fluid. RESULTS Plasma concentrations of free 25(OH)D over time were correlated with total 25(OH)D levels (r= 0.82; P < 0.001). The increase in free 25(OH)D was greater with the 500 000 IU vitamin D3 dose than with the lower dose. The percent change in mRNA expression of hCAP18 was positively associated with percent change in free 25(OH)D at days 7 and 14 (ρ = 0.48; P = 0.04 and ρ = 0.59; P = 0.03, respectively). Additionally, plasma LL-37 levels correlated with the percentage of alveolar macrophages exhibiting phagocytosis (ρ = 0.51; P = 0.04). CONCLUSIONS The present study found a dose-related increase in plasma free-25(OH)D levels, which was associated with increasing circulating mRNA expression of hCAP18 over time. There were no correlations between changes in total and free 25(OH)D against plasma LL-37 and hBD-2 concentrations. Larger studies appear warranted to determine the impact of high-dose vitamin D3 administration on endogenous AMPs.
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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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Leveraging family-specific signatures for AMP discovery and high-throughput annotation.
Waghu, FH, Barai, RS, Idicula-Thomas, S
Scientific reports. 2016;:24684
Abstract
Antimicrobial peptides (AMPs) are diverse, biologically active, essential components of the innate immune system. As compared to conventional antibiotics, AMPs exhibit broad spectrum antimicrobial activity, reduced toxicity and reduced microbial resistance. They are widely researched for their therapeutic potential, especially against multi-drug resistant pathogens. AMPs are known to have family-specific sequence composition, which can be mined for their discovery and rational design. Here, we present a detailed family-based study on AMP families. The study involved the use of sequence signatures represented by patterns and hidden Markov models (HMMs) present in experimentally studied AMPs to identify novel AMPs. Along with AMPs, peptides hitherto lacking antimicrobial annotation were also retrieved and wet-lab studies on randomly selected sequences proved their antimicrobial activity against Escherichia coli. CAMPSign, a webserver has been created for researchers to effortlessly exploit the use of AMP family signatures for identification of AMPs. The webserver is available online at www.campsign.bicnirrh.res.in. In this work, we demonstrate an optimised and experimentally validated protocol along with a freely available webserver that uses family-based sequence signatures for accelerated discovery of novel AMPs.
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High-Dose Probiotic Supplementation Containing Lactobacillus casei for 7 Days Does Not Enhance Salivary Antimicrobial Protein Responses to Exertional Heat Stress Compared With Placebo.
Gill, SK, Teixeira, AM, Rosado, F, Cox, M, Costa, RJ
International journal of sport nutrition and exercise metabolism. 2016;(2):150-60
Abstract
The study aimed to determine whether high-dose probiotic supplementation containing Lactobacillus casei (L. casei) for 7 consecutive days enhances salivary antimicrobial protein (S-AMP) responses to exertional-heat stress (EHS). Eight endurance-trained male volunteers (age 26 ± 6 years, nude body mass 70.2 ± 8.8 kg, height 1.75 ± 0.05 m, VO2max 59 ± 5 ml·kg-1·min-1 [M ± SD]) completed a blinded randomized and counterbalanced crossover design. Oral supplementation of the probiotic beverage (PRO; L. casei . 1011 colony-forming units·day-1) or placebo (PLA) was consumed for 7 consecutive days before 2 hr running exercise at 60% VO2max in hot ambient conditions (34.0° C and 32% RH). Body mass and unstimulated saliva and venous blood samples were collected at baseline (7 days before EHS), pre-EHS, post-EHS (1 hr, 2 hr, and 4 hr), and at 24 hr. Saliva samples were analyzed for salivary (S) IgA, α-amylase, lysozyme, and cortisol. Plasma samples were analyzed for plasma osmolality. Body mass and plasma osmolality did not differ between trials. Saliva flow rate remained relatively constant throughout the experimental design in PRO (overall M ± SD = 601 ± 284 μl/min) and PLA (557 ± 296 μl/min). PRO did not induce significant changes in resting S-AMP responses compared with PLA (p > .05). Increases in S-IgA, S-α-amylase, and S-cortisol responses, but not S-lysozyme responses, were observed after EHS (p < .05). No main effects of trial or Time x Trial interaction were observed for S-AMP and S-cortisol responses. Supplementation of a probiotic beverage containing L. casei for 7 days before EHS does not provide any further oral-respiratory mucosal immune protection, with respect to S-AMP, over PLA.
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Autophagy as a target for therapeutic uses of multifunctional peptides.
Muciño, G, Castro-Obregón, S, Hernandez-Pando, R, Del Rio, G
IUBMB life. 2016;(4):259-67
Abstract
The emergence of complex diseases is promoting a change from one-target to multitarget drugs and peptides are ideal molecules to fulfill this polypharmacologic role. Here we review current status in the design of polypharmacological peptides aimed to treat complex diseases, focusing on tuberculosis. In this sense, combining multiple activities in single molecules is a two-sided sword, as both positive and negative side effects might arise. These polypharmacologic compounds may be directed to regulate autophagy, a catabolic process that enables cells to eliminate intracellular microbes (xenophagy), such as Mycobacterium tuberculosis (MBT). Here we review some strategies to control MBT infection and propose that a peptide combining both antimicrobial and pro-autophagic activities would have a greater potential to limit MBT infection. This endeavor may complement the knowledge gained in understanding the mechanism of action of antibiotics and may lead to the design of better polypharmacological peptides to treat complex diseases such as tuberculosis.
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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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Experimental Induction of Bacterial Resistance to the Antimicrobial Peptide Tachyplesin I and Investigation of the Resistance Mechanisms.
Hong, J, Hu, J, Ke, F
Antimicrobial agents and chemotherapy. 2016;(10):6067-75
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Abstract
Tachyplesin I is a 17-amino-acid cationic antimicrobial peptide (AMP) with a typical cyclic antiparallel β-sheet structure that is a promising therapeutic for infections, tumors, and viruses. To date, no bacterial resistance to tachyplesin I has been reported. To explore the safety of tachyplesin I as an antibacterial drug for wide clinical application, we experimentally induced bacterial resistance to tachyplesin I by using two selection procedures and studied the preliminary resistance mechanisms. Aeromonas hydrophila XS91-4-1, Pseudomonas aeruginosa CGMCC1.2620, and Escherichia coli ATCC 25922 and F41 showed resistance to tachyplesin I under long-term selection pressure with continuously increasing concentrations of tachyplesin I. In addition, P. aeruginosa and E. coli exhibited resistance to tachyplesin I under UV mutagenesis selection conditions. Cell growth and colony morphology were slightly different between control strains and strains with induced resistance. Cross-resistance to tachyplesin I and antimicrobial agents (cefoperazone and amikacin) or other AMPs (pexiganan, tachyplesin III, and polyphemusin I) was observed in some resistant mutants. Previous studies showed that extracellular protease-mediated degradation of AMPs induced bacterial resistance to AMPs. Our results indicated that the resistance mechanism of P. aeruginosa was not entirely dependent on extracellular proteolytic degradation of tachyplesin I; however, tachyplesin I could induce increased proteolytic activity in P. aeruginosa Most importantly, our findings raise serious concerns about the long-term risks associated with the development and clinical use of tachyplesin I.
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Diagnostic accuracy of urine heparin binding protein for pediatric acute pyelonephritis.
Lertdumrongluk, K, Thongmee, T, Kerr, SJ, Theamboonlers, A, Poovorawan, Y, Rianthavorn, P
European journal of pediatrics. 2015;(1):43-8
Abstract
UNLABELLED Timely antibiotic initiation for acute pyelonephritis (APN) can prevent renal complications. We investigated whether urine heparin binding protein (UHBP), a cytokine released from activated neutrophils, was a useful diagnostic tool for APN. Febrile children with presumed APN were prospectively enrolled between January and September 2013, and divided into two groups based on urine cultures. UHBP levels were measured at enrollment in all children and 1 month after antibiotic treatment in children with APN. UHBP levels in children with APN at baseline and 1 month versus controls were 47.0 ± 8.4 and 16.6 ± 3.8 vs. 15.0 ± 2.9 ng/mL, respectively (p < 0.001). Test performance characteristics were calculated against a gold standard of positive urine cultures and compared with leukocyte esterase (LE) and nitrite measured by dipsticks and pyuria by microscopy. The sensitivity and specificity for UHBP levels ≥34 ng/mL were 100 and 100 %. Spearman's rank coefficient was used to assess the associations between routine laboratory tests and UHBP levels. Significant positive correlations were found with pyuria grade (Spearman's rho = 0.62; p < 0.001), neutrophil count (rho = 0.38; p = 0.03), and platelet count (rho = 0.39; p = 0.03). CONCLUSIONS UHBP is a valid adjunctive diagnostic tool for aiding clinicians in making rapid treatment decisions for APN.
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Nasal Levels of Antimicrobial Peptides in Allergic Asthma Patients and Healthy Controls: Differences and Effect of a Short 1,25(OH)2 Vitamin D3 Treatment.
Thijs, W, Janssen, K, van Schadewijk, AM, Papapoulos, SE, le Cessie, S, Middeldorp, S, Melissant, CF, Rabe, KF, Hiemstra, PS
PloS one. 2015;(11):e0140986
Abstract
BACKGROUND Allergy is often accompanied by infections and lower levels of antimicrobial peptides (AMPs). Vitamin D has been shown to increase expression of selected AMPs. In this study we investigated whether antimicrobial peptide levels in nasal secretions of allergic asthma patients are lower than in healthy controls, and whether administration of the active form of vitamin D (1,25(OH)2D3) affects these antimicrobial peptide levels. METHODS The levels of antimicrobial peptides in nasal secretions were compared between 19 allergic asthma patients and 23 healthy controls. The effect of seven days daily oral treatment with 2 μg 1,25(OH)2D3 on antimicrobial peptides in nasal secretions was assessed in a placebo-controlled cross-over clinical study. RESULTS Levels of neutrophil α-defensins (human neutrophil peptides 1-3; HNP1-3) and lipocalin 2 (LCN2; also known as NGAL) were significantly lower in asthmatics, but no differences in LL-37 and SLPI were detected. Treatment with a short-term 1,25(OH)2D3 caused a small increase in HNP1-3, but not when the asthma and control groups were analyzed separately. LL-37, LCN2 and SLPI did not change after treatment with 1,25(OH)2D3. CONCLUSION Levels of the antimicrobial peptides HNP1-3 and LCN2 are lower in nasal secretions in asthmatics and are not substantially affected by a short-term treatment with active vitamin D.