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Antimicrobial peptides (AMPs) are essential components of innate immunity across all species. AMPs have become the focus of attention in recent years, as scientists are addressing antibiotic resistance, a public health crisis that has reached epidemic proportions. This family of peptides represents a promising alternative to current antibiotics due to their broad-spectrum antimicrobial activity and tendency to avoid resistance development. A subfamily of AMPs interacts with metal ions to potentiate antimicrobial effectiveness, and, as such, they have been termed metalloAMPs. In this work, we review the scientific literature on metalloAMPs that enhance their antimicrobial efficacy when combined with the essential metal ion zinc(II). Beyond the role played by Zn(II) as a cofactor in different systems, it is well-known that this metal ion plays an important role in innate immunity. Here, we classify the different types of synergistic interactions between AMPs and Zn(II) into three distinct classes. By better understanding how each class of metalloAMPs uses Zn(II) to potentiate its activity, researchers can begin to exploit these interactions in the development of new antimicrobial agents and accelerate their use as therapeutics. [ABSTRACT FROM AUTHOR]

Increased antibiotic resistance poses a major limitation in tackling inflammatory bowel disease and presents a large challenge for global health care. Antimicrobial peptides (AMPs) are a potential class of antimicrobial agents. Here, we have designed the potential oral route for antimicrobial peptide R7I with anti‐proteolytic properties to deal with bacterial enteritis in mice. The results revealed that R7I protected the liver and gut from damage caused by inflammation. RNA‐Seq analysis indicated that R7I promoted digestion and absorption in the small intestine by upregulating transmembrane transporter activity, lipid and small molecule metabolic processes and other pathways, in addition to upregulating hepatic steroid biosynthesis and fatty acid degradation. For the gut microbiota, Clostridia were significantly reduced in the R7I‐treated group, and Odoribacteraceae, an efficient isoalloLCA‐synthesizing strain, was the main dominant strain, protecting the gut from potential pathogens. In addition, we further discovered that R7I reduced the accumulation of negative organic acid metabolites. Overall, R7I exerted better therapeutic and immunomodulatory potential in the bacterial enteritis model, greatly reduced the risk of disease onset, and provided a reference for the in vivo application of antimicrobial peptides. [ABSTRACT FROM AUTHOR]

Heightened attention to police brutality has created momentum for alternative, community-based responses to violence, including that inflicted by an intimate partner. But to build effective alternatives, we must know what survivors already do in moments of acute danger when they do not call the police. This study sought to explore these moments from an ecological perspective. Using a qualitative descriptive methodology, we conducted 25 interviews with a diverse sample of intimate partner violence (IPV) survivors. Each described the first, the worst, and the most recent IPV incident, whom they reached out to and why, the outcomes of their help-seeking, and the individual, interpersonal, and psychosocial influences on the process. Even in the face of severe violence, what participants most wanted was someone who would listen without judgment. Direct interpersonal factors that influenced their help-seeking included their partner's controlling behavior, as well as their network members' capacities, perspectives on IPV, and feelings about the survivor. Broader influential factors included the radiating effects of IPV and other forms of trauma in survivors' networks. Participants offered recommendations on how domestic violence (DV) programs could both strengthen survivors' networks and provide them with targeted community support in moments of grave danger. As we continue to develop community-based alternatives to police intervention, DV programs have a critical opportunity to build on survivors' own recommendations. This process must address the ongoing effects of trauma that hamper the ability of so many network members to support survivors in crisis. [ABSTRACT FROM AUTHOR]

Cathelicidin antimicrobial peptides (mouse, CRAMP; human, LL-37) have broad-spectrum antiviral activities against enveloped viruses, but their mechanisms of action against nonenveloped viruses remain to be elucidated. Coxsackievirus B3 (CVB3), a member of nonenveloped virus belonging to the Enterovirus genus of Picornaviridae, is an important pathogen of viral myocarditis and dilated cardiomyopathy. Here, we observed that cardiac CRAMP expression was significantly upregulated in mice after CVB3 infection. The administration of CRAMP or LL-37 markedly suppressed CVB3 infection in mice, and CRAMP deficiency increased the susceptibility of mice to CVB3. CRAMP and LL-37 inhibited CVB3 replication in primary cardiomyocytes. However, they did not inactivate CVB3 particles and did not regulate the response of cardiomyocytes against CVB3 infection. Intriguingly, they inhibited CVB3 transmission through the exosome, but not virus receptor. In detail, CRAMP and LL-37 directly induced the lysis of exosomes by interfering with exosomal heat shock protein 60 (HSP60) and then blocked the diffusion of exosomes to recipient cells and inhibited the establishment of productive infection by exosomes. In addition, the interaction of CRAMP and LL-37 with HSP60 simultaneously inhibited HSP60-induced apoptosis in cardiomyocytes and reduced HSP60-enhanced CVB3 replication. Our findings reveal a novel mechanism of cathelicidins against viral infection and provide a new therapeutic strategy for CVB3-induced viral myocarditis. IMPORTANCE The relative mechanisms that cathelicidin antimicrobial peptides use to influence nonenveloped virus infection are unclear. We show here that cathelicidin antimicrobial peptides (CRAMP and LL-37) directly target exosomal HSP60 to destroy exosomes, which in turn block the diffusion of exosomes to recipient cardiomyocytes and reduced HSP60-induced apoptosis, thus restricting coxsackievirus B3 infection. Our results provide new insights into the mechanisms cathelicidin antimicrobial peptides use against viral infection. [ABSTRACT FROM AUTHOR]

The byproducts of bacterial fermentation known as short-chain fatty acids (SCFAs) are chemically comprised of a carboxylic acid component and a short hydrocarbon chain. Recent investigations have demonstrated that SCFAs can affect intestinal immunity by inducing endogenous host defense peptides (HDPs) and their beneficial effects on barrier integrity, gut health, energy supply, and inflammation. HDPs, which include defensins, cathelicidins, and C-type lectins, perform a significant function in innate immunity in gastrointestinal mucosal membranes. SCFAs have been demonstrated to stimulate HDP synthesis by intestinal epithelial cells via interactions with G protein-coupled receptor 43 (GPR43), activation of the Jun N-terminal kinase (JNK) and Mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways, and the cell growth pathways. Furthermore, SCFA butyrate has been demonstrated to enhance the number of HDPs released from macrophages. SCFAs promote monocyte-to-macrophage development and stimulate HDP synthesis in macrophages by inhibiting histone deacetylase (HDAC). Understanding the etiology of many common disorders might be facilitated by studies into the function of microbial metabolites, such as SCFAs, in the molecular regulatory processes of immune responses (e.g., HDP production). This review will focus on the current knowledge of the role and mechanism of microbiota-derived SCFAs in influencing the synthesis of host-derived peptides, particularly HDPs.

A subset of dermal fibroblasts undergo rapid differentiation into adipocytes in response to infection and acutely produce the cathelicidin antimicrobial peptide gene Camp Vitamin A and other retinoids inhibit adipogenesis yet can show benefit to skin disorders, such as cystic acne, that are exacerbated by bacteria. We observed that retinoids potently increase and sustain the expression of Camp in preadipocytes undergoing adipogenesis despite inhibition of markers of adipogenesis, such as Adipoq, Fabp4, and Rstn Retinoids increase cathelicidin in both mouse and human preadipocytes, but this enhancement of antimicrobial peptide expression did not occur in keratinocytes or a sebocyte cell line. Preadipocytes undergoing adipogenesis more effectively inhibited growth of Staphylococcus aureus when exposed to retinoic acid. Whole transcriptome analysis identified hypoxia-inducible factor 1-α (HIF-1α) as a mechanism through which retinoids mediate this response. These observations uncouple the lipid accumulation element of adipogenesis from the innate immune response and uncover a mechanism, to our knowledge previously unsuspected, that may explain therapeutic benefits of retinoids in some skin disorders.

Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major health care concern, especially infective endocarditis (IE). Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as "resistant" to β-lactams, often leading to the use of costly and/or toxic treatment regimens. In this investigation, five prototype MRSA strains, representing the range of genotypes in current clinical circulation, were studied. We identified two distinct MRSA phenotypes upon AST using standard media, with or without sodium bicarbonate (NaHCO3) supplementation: one highly susceptible to the antistaphylococcal β-lactams oxacillin and cefazolin (NaHCO3 responsive) and one resistant to such agents (NaHCO3 nonresponsive). These phenotypes accurately predicted clearance profiles of MRSA from target tissues in experimental MRSA IE treated with each β-lactam. Mechanistically, NaHCO3 reduced the expression of two key genes involved in the MRSA phenotype, mecA and sarA, leading to decreased production of penicillin-binding protein 2a (that mediates methicillin resistance), in NaHCO3-responsive (but not in NaHCO3-nonresponsive) strains. Moreover, both cefazolin and oxacillin synergistically killed NaHCO3-responsive strains in the presence of the host defense antimicrobial peptide (LL-37) in NaHCO3-supplemented media. These findings suggest that AST of MRSA strains in NaHCO3-containing media may potentially identify infections caused by NaHCO3-responsive strains that are appropriate for β-lactam therapy.

DC, through the uptake, processing, and presentation of antigen, are responsible for activation of T cell responses to defend the host against infection, yet it is not known if they can directly kill invading bacteria. Here, we studied in human leprosy, how Langerhans cells (LC), specialized DC, contribute to host defense against bacterial infection. IFN-γ treatment of LC isolated from human epidermis and infected with Mycobacterium leprae (M. leprae) activated an antimicrobial activity, which was dependent on the upregulation of the antimicrobial peptide cathelicidin and induction of autophagy. IFN-γ induction of autophagy promoted fusion of phagosomes containing M. leprae with lysosomes and the delivery of cathelicidin to the intracellular compartment containing the pathogen. Autophagy enhanced the ability of M. leprae-infected LC to present antigen to CD1a-restricted T cells. The frequency of IFN-γ labeling and LC containing both cathelicidin and autophagic vesicles was greater in the self-healing lesions vs. progressive lesions, thus correlating with the effectiveness of host defense against the pathogen. These data indicate that autophagy links the ability of DC to kill and degrade an invading pathogen, ensuring cell survival from the infection while facilitating presentation of microbial antigens to resident T cells.

The gastrointestinal tract is a complex environment in which the host immune system interacts with a diverse array of microorganisms, both symbiotic and pathogenic. As such, mobilizing a rapid and appropriate antimicrobial response depending on the nature of each stimulus is crucial for maintaining the balance between homeostasis and inflammation in the gut. Here we focus on the mechanisms by which intestinal antimicrobial peptides regulate microbial communities during dysbiosis and infection. We also discuss classes of bacterial peptides that contribute to reducing enteric pathogen outgrowth. This review aims to provide a comprehensive overview on the interplay of diverse antimicrobial responses with enteric pathogens and the gut microbiota.

Antimicrobial peptides (AMPs) are typically thought of as molecular hole punchers that directly kill pathogens by membrane permeation. However, recent work has shown that AMPs are pleiotropic, multifunctional molecules that can strongly modulate immune responses. In this review, we provide a historical overview of the immunomodulatory properties of natural and synthetic antimicrobial peptides, with a special focus on human cathelicidin and defensins. We also summarize the various mechanisms of AMP immune modulation and outline key structural rules underlying the recently-discovered phenomenon of AMP-mediated Toll-like receptor (TLR) signaling. In particular, we describe several complementary studies demonstrating how AMPs self-assemble with nucleic acids to form nanocrystalline complexes that amplify TLR-mediated inflammation. In a broader scope, we discuss how this new conceptual framework allows for the prediction of immunomodulatory behavior in AMPs, how the discovery of hidden antimicrobial activity in known immune signaling proteins can inform these predictions, and how these findings reshape our understanding of AMPs in normal host defense and autoimmune disease.

Amphiphilicity in ɑ-helical antimicrobial peptides (AMPs) is recognized as a signature of potential membrane activity. Some AMPs are also strongly immunomodulatory: LL37-DNA complexes potently amplify Toll-like receptor 9 (TLR9) activation in immune cells and exacerbate autoimmune diseases. The rules governing this proinflammatory activity of AMPs are unknown. Here we examine the supramolecular structures formed between DNA and three prototypical AMPs using small angle X-ray scattering and molecular modeling. We correlate these structures to their ability to activate TLR9 and show that a key criterion is the AMP's ability to assemble into superhelical protofibril scaffolds. These structures enforce spatially-periodic DNA organization in nanocrystalline immunocomplexes that trigger strong recognition by TLR9, which is conventionally known to bind single DNA ligands. We demonstrate that we can "knock in" this ability for TLR9 amplification in membrane-active AMP mutants, which suggests the existence of tradeoffs between membrane permeating activity and immunomodulatory activity in AMP sequences.

The collective tolerance towards antimicrobial peptides (APs) is thought to occur primarily through mechanisms associated with live bacterial cells. In contrast to the focus on live cells, we discover that the LL37 antimicrobial peptide kills a subpopulation of Escherichia coli, forming dead cells that absorb the remaining LL37 from the environment. Combining mathematical modelling with population and single-cell experiments, we show that bacteria absorb LL37 at a timing that coincides with the permeabilization of their cytoplasmic membranes. Furthermore, we show that one bacterial strain can absorb LL37 and protect another strain from killing by LL37. Finally, we demonstrate that the absorption of LL37 by dead bacteria can be reduced using a peptide adjuvant. In contrast to the known collective tolerance mechanisms, we show that the absorption of APs by dead bacteria is a dynamic process that leads to emergent population behaviour.

Dermal fibroblasts (dFBs) resist infection by locally differentiating into adipocytes and producing cathelicidin antimicrobial peptide in response to Staphylococcus aureus (S. aureus). Here, we show that neonatal skin was enriched with adipogenic dFBs and immature dermal fat that highly expressed cathelicidin. The pool of adipogenic and antimicrobial dFBs declined after birth, leading to an age-dependent loss of dermal fat and a decrease in adipogenesis and cathelidicin production in response to infection. Transforming growth factor beta (TGF-β), which acted on uncommitted embryonic and adult dFBs and inhibited their adipogenic and antimicrobial function, was identified as a key upstream regulator of this process. Furthermore, inhibition of the TGF-β receptor restored the adipogenic and antimicrobial function of dFBs in culture and increased resistance of adult mice to S. aureus infection. These results provide insight into changes that occur in the skin innate immune system between the perinatal and adult periods of life.

BackgroundRosacea is a chronic inflammatory skin condition whose etiology has been linked to mast cells and the antimicrobial peptide cathelicidin LL-37. Individuals with refractory disease have demonstrated clinical benefit with periodic injections of onabotulinum toxin, but the mechanism of action is unknown.ObjectivesTo investigate the molecular mechanism by which botulinum toxin improves rosacea lesions.MethodsPrimary human and murine mast cells were pretreated with onabotulinum toxin A or B or control. Mast cell degranulation was evaluated by β-hexosaminidase activity. Expression of botulinum toxin receptor Sv2 was measured by qPCR. The presence of SNAP-25 and VAMP2 was established by immunofluorescence. In vivo rosacea model was established by intradermally injecting LL-37 with or without onabotulinum toxin A pretreatment. Mast cell degranulation was assessed in vivo by histologic counts. Rosacea biomarkers were analyzed by qPCR of mouse skin sections.ResultsOnabotulinum toxin A and B inhibited compound 48/80-induced degranulation of both human and murine mast cells. Expression of Sv2 was established in mouse mast cells. Onabotulinum toxin A and B increased cleaved SNAP-25 and decreased VAMP2 staining in mast cells respectively. In mice, injection of onabotulinum toxin A significantly reduced LL-37-induced skin erythema, mast cell degranulation, and mRNA expression of rosacea biomarkers.ConclusionsThese findings suggest that onabotulinum toxin reduces rosacea-associated skin inflammation by directly inhibiting mast cell degranulation. Periodic applications of onabotulinum toxin may be an effective therapy for refractory rosacea and deserves further study.

Recent studies using I lepr i SP I db i sp mice to model diabetic infection showed that diabetic mice are more susceptible to GBS skin wound infection and that GBS triggers a hyper-inflammatory environment in the wound [[11]]. I Streptococcus agalactiae i (Group B I Streptococcus i , GBS) is a gram-positive pathobiont that colonizes the gastrointestinal and urogenital tracts of approximately 25% of individuals. In addition, respiration metabolism leads to the accumulation of the major GBS nuclease NucA, which contributes to degradation of neutrophil extracellular traps (NETs) and virulence in the lung [[17]] and is speculated to promote GBS survival in the diabetic wound [[11]], although this has not yet been shown. GBS regulation in diabetic infection To determine how GBS responds to elevated glucose, Di Palo and colleagues performed transcriptomic analysis on GBS grown in medium without or with glucose (55 mM) for 30 min [[20]]. [Extracted from the article]

Simple Summary: Cancer immunotherapies using antibodies and genetically modified T cells are effective in a subset of cancer patients. However, many cancer patients do not respond to immunotherapy because their cancers induce cells called myeloid-derived suppressor cells (MDSCs) that antagonize the immune system. Clinical and animal studies indicate that non-responding cancer patients have elevated levels of MDSCs. Therefore, a better understanding of the mechanisms that drive the accumulation and function of MDSCs may lead to improved cancer therapies. This article summarizes the role of an important receptor (RAGE: receptor for advanced glycation endproducts) and its two dominant ligands (S100A8/A9 and high mobility group box protein 1 (HMGB1)) that induce the accumulation and increase the immune suppressive function of MDSCs. S100A8/A9 and HMGB1 are potential biomarkers for the accumulation of MDSCs and their neutralization and/or the inhibition of RAGE may enhance cancer immunotherapies. Immunotherapies including checkpoint blockade immunotherapy (CBI) and chimeric antigen receptor T cells (CAR-T) have revolutionized cancer treatment for patients with certain cancers. However, these treatments are not effective for all cancers, and even for those cancers that do respond, not all patients benefit. Most cancer patients have elevated levels of myeloid-derived suppressor cells (MDSCs) that are potent inhibitors of antitumor immunity, and clinical and animal studies have demonstrated that neutralization of MDSCs may restore immune reactivity and enhance CBI and CAR-T immunotherapies. MDSCs are homeostatically regulated in that elimination of mature circulating and intratumoral MDSCs results in increased production of MDSCs from bone marrow progenitor cells. Therefore, targeting MDSC development may provide therapeutic benefit. The pro-inflammatory molecules S100A8/A9 and high mobility group box protein 1 (HMGB1) and their receptor RAGE are strongly associated with the initiation and progression of most cancers. This article summarizes the literature demonstrating that these molecules are integrally involved in the early development, accumulation, and suppressive activity of MDSCs, and postulates that S100A8/A9 and HMGB1 serve as early biomarkers of disease and in conjunction with RAGE are potential targets for reducing MDSC levels and enhancing CBI and CAR-T immunotherapies. [ABSTRACT FROM AUTHOR]

Simple Summary: A critical global health problem is microbial resistance to antibiotics. In order to further discuss this issue and search for practical means to overcome such problems, we reviewed the bibliography related to snake venoms, their proteins, and peptides with antimicrobial activity because many of them have the potential to become alternative antimicrobial agents or serve as lead compounds for the development of new ones. Among the proteins classified according to their structures are lectins, metalloproteinases, L-amino acid oxidases, phospholipases type A2, cysteine-rich secretory proteins, and serine proteinases. Among the oligopeptides are waprins, cardiotoxins, cathelicidins, and β-defensins. The list includes natural and synthetic small peptides, many derived from the proteins and the oligopeptides cited above. In vitro, all these snake-venom components are active against bacteria, fungi, parasites, and/or viruses pathogenic to humans. Some have also been tested in laboratory animals. In addition to organizing and discussing such an expressive amount of information, we propose here a multidisciplinary approach that includes sequence phylogeny as a way to better understand the relationship between amino-acid sequence and antimicrobial activity. 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. [ABSTRACT FROM AUTHOR]

CuSO4 was used and created an in-vivo inflammatory model of a zebrafish embryo for drug testing in this work. In our study, molecular docking was performed to check the possible polar interaction with the peptide, TL15 of sulphite reductase derived from spirulina (Arthrospira plantensis) and the COX-2, which is predicted to have anti-inflammatory activity. In-vitro anti-inflammatory activity was performed on human erythrocytes, and the potential activity of TL15 peptide was in a concentration-dependent manner. We further investigated the technique for evaluating the anti-inflammatory effects of TL15. To produce acute inflammation, the zebrafish (Danio rerio) larvae were treated with CuSO4 at 2 μM and toxicity analysis were done at 0–96 hpf. The effect of TL15 was analysed upon treatment to CuSO4 induced larvae at dose-dependent manner (10–80 μM) and exhibited a gradual reduction in oxidative stress at 80 μM TL15. Macrophages were monitored using neutral red labelling after CuSO4 stimulation; as the major end-point, larval mortality was employed. RT-PCR was used to assess the expression level of important cytokines implicated in the inflammatory response, such as COX-2, TNF-α, IL-1β and IL-10. Within 24 h, CuSO4 increased mortality in a dose-dependent process. The increment in the inflammatory response due to CuSO4 induction in zebrafish larvae was demonstrated by analysing the COX-2, IL-1β, IL-10 and TNF-α expression. In addition, we also investigated the reactive oxygen species scavenging activity of TL15 on CuSO4 induced larvae by analysing the GST and GPX expression levels in the zebrafish embryo. Overall, TL15 of sulphite reductase was found to have a potent anti-inflammatory activity by scavenging the free radical productions. [ABSTRACT FROM AUTHOR]

Aims A rapid rise in resistance to conventional antibiotics for Shigella spp. has created a problem in treating shigellosis. Hence, there is an urgent need for new and non-conventional anti-bacterial agents. The aim of this study is to show how Asiatic acid, a plant-derived compound, inhibits the intracellular growth of Shigella flexneri. Methods and results Shigella flexneri sensitive and resistant strains were used for checking antimicrobial activity of Asiatic acid by gentamicin protection assay. Asiatic acid inhibited the intracellular growth of all strains. Gene expression analysis showed antimicrobial peptide (AMP) up-regulation by Asiatic acid in intestinal cells. Further western blot analysis showed that ERK, p38, and JNK are activated by Asiatic acid. ELISA was performed to check IL-8, IL-6, and cathelicidin secretion. The antibacterial effect of Asiatic acid was further verified in an in vivo mouse model. Conclusions The reason behind the antibacterial activities of Asiatic acid is probably over-expression of antimicrobial peptide genes. Besides, direct antimicrobial activities, antimicrobial peptides also carry immunomodulatory activities. Here, Asiatic acid increased IL-6 and IL-8 secretion to induce inflammation. Overall, Asiatic acid up-regulates antimicrobial peptide gene expression and inhibits intracellular S. flexneri growth. Moreover, Asiatic acid reduced bacterial growth and recovered intestinal tissue damages in in vivo mice model. [ABSTRACT FROM AUTHOR]

Multidrug-resistant tuberculosis (MDR) continues to pose a threat to public health. Previously, we identified a cationic host defense peptide with activity against Mycobacterium tuberculosis in vivo and with a bactericidal effect against MDR M. tuberculosis at therapeutic concentrations. To understand the mechanisms of this peptide, we investigated its interactions with live M. tuberculosis and liposomes as a model. Peptide interactions with M. tuberculosis inner membranes induced tube-shaped membranous structures and massive vesicle formation, thus leading to bubbling cell death and ghost cell formation. Liposomal studies revealed that peptide insertion into inner membranes induced changes in the peptides' secondary structure and that the membranes were pulled such that they aggregated without permeabilization, suggesting that the peptide has a strong inner membrane affinity. Finally, the peptide targeted essential proteins in M. tuberculosis, such as 60 kDa chaperonins and elongation factor Tu, that are involved in mycolic acid synthesis and protein folding, which had an impact on bacterial proliferation. The observed multifaceted targeting provides additional support for the therapeutic potential of this peptide. [ABSTRACT FROM AUTHOR]

We performed structural and functional studies of minibactenecin mini-ChBac7.5Nα, a natural proline-rich cathelicidin from domestic goat Capra hircus. To identify the key residues important for the biological action of the peptide, a panel of its alanine-substituted analogues was produced. The development of E. coli resistance to the natural minibactenecin, as well as to its analogues carrying substitutions for hydrophobic amino acids in the C-terminal residues was studied. The data obtained indicate the possibility of rapid development of the resistance to this class of peptides. The main factors in the formation of the antibiotic resistance are various mutations leading to inactivation of the SbmA transporter. [ABSTRACT FROM AUTHOR]

The article discusses a research study conducted to develop effective antibacterial agents to induce antimicrobial resistance as drug-resistant bacterial infections cause serious threats to human health. It is noted that host defense peptides (HDPs) are believed as promising candidates in developing antimicrobials owing to its broad-spectrum antibacterial activity and insusceptibility to antimicrobial resistance.

Background: A number of antimicrobial peptides (AMPs) hold promise as new drugs owing to their potent bactericidal activity and because they are often refractory to the development of drug resistance. Cryptdins (Crps) are a family of antimicrobial peptides found in the small intestine of mice, comprising six isoforms containing three sets of disulfide bonds. Although Crp4 is actively being investigated, there have been few studies to date on the other Crp isoforms. A prerequisite for detailed characterization of the other Crp isoforms is establishment of efficient sample preparation methods. Results: To avoid degradation during recombinant expression of Crps in E. coli, co-expression of Crps with the aggregation-prone protein human α-lactalbumin (HLA) was used to promote the formation of stable inclusion bodies. Using this method, the production of Crp4 and Crp6 by the BL21 strain was effective, but the expression of other Crp isoforms was not as efficient. The results of a cell-free system study suggested that Crps were degraded, even though a substantial amounts of Crps were synthesized. Therefore, using the Origami™ B strain, we were able to significantly increase the expression efficiency of Crps by promoting the formation of erroneous intermolecular disulfide bonds between HLA and Crps, thereby promoting protein aggregation and inclusion body formation, which prevented degradation. The various Crp isoforms were successfully refolded in vitro and purified using reversed-phase HPLC. In addition, the yield was further improved by deformylation of formyl-Crps. We measured the antibacterial activity of Crps against both Gram-positive and Gram-negative bacteria. Each Crp isoform exhibited a completely different trend in antimicrobial activity, although conformational analysis by circular dichroism did not reveal any significant steric differences. Conclusion: In this study, we established a novel and efficient method for the production of the cryptdin family of cysteine-containing antimicrobial peptides. Additionally, we found that there were notable differences in the antibacterial activities of the various Crp family members. The expression system established in this study is expected to provide new insights regarding the mechanisms underlying the different antibacterial activities of the Crp family of peptides. [ABSTRACT FROM AUTHOR]

Solid‐state NMR (ssNMR) spectroscopy facilitates the non‐destructive characterization of structurally heterogeneous biomolecules in their native setting, for example, comprising proteins, lipids and polysaccharides. Here we demonstrate the utility of high and ultra‐high field 1H‐detected fast MAS ssNMR spectroscopy, which exhibits increased sensitivity and spectral resolution, to further elucidate the atomic‐level composition and structural arrangement of the cell wall of Schizophyllum commune, a mushroom‐forming fungus from the Basidiomycota phylum. These advancements allowed us to reveal that Cu(II) ions and the antifungal peptide Cathelicidin‐2 mainly bind to cell wall proteins at low concentrations while glucans are targeted at high metal ion concentrations. In addition, our data suggest the presence of polysaccharides containing N‐acetyl galactosamine (GalNAc) and proteins, including the hydrophobin proteins SC3, shedding more light on the molecular make‐up of cells wall as well as the positioning of the polypeptide layer. Obtaining such information may be of critical relevance for future research into fungi in material science and biomedical contexts. [ABSTRACT FROM AUTHOR]

Fast healing of diabetic wounds remains a major clinical challenge. Herein, this study reports a strategy to combine nanofiber aerogels containing precision macrochannels and the LL‐37‐mimic peptide W379 for rapid diabetic wound healing. Nanofiber aerogels consisting of poly(glycolide‐co‐lactide) (PGLA 90:10)/gelatin and poly‐p‐dioxanone (PDO)/gelatin short electrospun fiber segments are prepared by partially anisotropic freeze‐drying, cross‐linking, and sacrificial templating with 3D printed meshes, exhibiting nanofibrous architecture and precision micro‐/macrochannels. Like human cathelicidin LL‐37, W379 peptide at a concentration of 3 µg mL−1 enhances the migration and proliferation of keratinocytes and dermal fibroblasts in a cell scratch assay and a proliferation assay. In vivo studies show that nanofiber aerogels with precision macrochannels can greatly promote cell penetration compared to aerogels without macrochannels. Relative to control and aerogels with and without macrochannels, adding W379 peptides to aerogels with precision macrochannels shows the best efficacy in healing diabetic wounds in mice in terms of cell infiltration, neovascularization, and re‐epithelialization. The fast re‐epithelization could be due to the upregulation of phospho‐extracellular signal‐regulated kinase (p38 mitogen‐activated protein kinase) after treatment with W379. Together, the approach developed in this study could be promising for the treatment of diabetic wounds and other chronic wounds. [ABSTRACT FROM AUTHOR]

Shrimp antilipopolysaccharide factors (ALFs) form a multifunctional and diverse family of antimicrobial host defense peptides (AMPs) composed of seven members (groups A to G), which differ in terms of their primary structure and biochemical properties. They are amphipathic peptides with two conserved cysteine residues stabilizing a central β-hairpin that is understood to be the core region for their biological activities. In this study, we synthetized three linear (cysteine-free) peptides based on the amino acid sequence of the central β-hairpin of the newly identified shrimp (Litopenaeus vannamei) ALFs from groups E to G. Unlike whole mature ALFs, the ALF-derived peptides exhibited an α-helix secondary structure. In vitro assays revealed that the synthetic peptides display a broad spectrum of activity against both Gram-positive and Gram-negative bacteria and fungi but not against the protozoan parasites Trypanosoma cruzi and Leishmania (L.) infantum. Remarkably, they displayed synergistic effects and showed the ability to permeabilize bacterial membranes, a mechanism of action of classical AMPs. Having shown low cytotoxicity to THP-1 human cells and being active against clinical multiresistant bacterial isolates, these nature-inspired peptides represent an interesting class of bioactive molecules with biotechnological potential for the development of novel therapeutics in medical sciences. [ABSTRACT FROM AUTHOR]

An active form of cathelicidin antimicrobial peptide, LL-37, has immunomodulatory and stimulatory effects, though the specific pathways are not clear. The purpose of this study was to identify the cellular pathways by which LL-37 amplifies the inflammation induced by damage-associated molecular patterns (DAMPs). We performed DNA microarray, reverse transcription polymerase chain reaction, immunoblotting, and proximity ligation assays using cultured keratinocytes treated with LL-37 and/or the DAMP poly(I:C), a synthetic double-stranded RNA. In contrast to the combination of LL-37 and poly(I:C), LL-37 alone induced genes related to biological metabolic processes such as VEGFA and PTGS2 (COX-2). Inhibition of FPR2, a known receptor for cathelicidin, partially suppressed the induction of VEGFA and PTGS2. Importantly, VEGFA and PTGS2 induced by LL-37 alone were diminished by the knockdown of scavenger receptors including SCARB1 (SR-B1), OLR1 (SR-E1), and AGER (SR-J1). Moreover, LL-37 alone, as well as the combination of LL-37 and poly(I:C), showed proximity to the scavenger receptors, indicating that LL-37 acts via scavenger receptors and intermediates between them and poly(I:C). These results showed that the broad function of cathelicidin is generally dependent on scavenger receptors. Therefore, inhibitors of scavenger receptors or non-functional mock cathelicidin peptides may serve as new anti-inflammatory and immunosuppressive agents. [ABSTRACT FROM AUTHOR]

Host defense peptides are found primarily as natural antimicrobial agents among all lifeforms. These peptides and their synthetic derivatives have been extensively studied for their potential use as therapeutic agents. The most accepted mechanism of action of these peptides is related to a nonspecific mechanism associated with their interaction with the negatively charged groups present in membranes, inducing bilayer destabilization and cell death through several routes. Among the most recently reported peptides, LTX-315 has emerged as an important oncolytic peptide that is currently in several clinical trials against different cancer types. However, there is a lack of biophysical studies regarding LTX-315 and its interaction with membranes. This research focuses primarily on the understanding of the molecular bases of LTX-315′s interaction with eukaryotic lipids, based on two artificial systems representative of non-tumoral and tumoral membranes. Additionally, the interaction with individual lipids was studied by differential scanning calorimetry and Fourier-transformed infrared spectroscopy. The results showed a strong interaction of LTX-315 with the negatively charged phosphatidylserine. The results are important for understanding and facilitating the design and development of improved peptides with anticancer activity. [ABSTRACT FROM AUTHOR]

New antimicrobial agents are urgently needed to address the increasing emergence and dissemination of multidrug-resistant bacteria. In the study, a chemically synthesized truncated peptide containing 22-amino acids derived from a C-type lectin homolog SpCTL6 of Scylla paramamosain was screened and found to exhibit broad-spectrum antimicrobial activity, indicating that it is an antimicrobial peptide (AMP), named Sp-LECin. Sp-LECin possessed the basic characteristics of most cationic AMPs, such as positive charge (+4) and a relatively high hydrophobicity (45%). After treatment with Sp-LECin, the disruption of microbial membrane integrity and even leakage of cellular contents was observed by scanning electron microscopy (SEM). In addition, Sp-LECin could bind lipopolysaccharide (LPS), increase the outer and inner membrane permeability and induce reactive oxygen species (ROS) production, ultimately leading to the death of Pseudomonas aeruginosa. Furthermore, Sp-LECin exhibited potent anti-biofilm activity against P. aeruginosa during both biofilm formation and maturation. Notably, Sp-LECin had no obvious cytotoxicity and could greatly improve the survival of P. aeruginosa-infected zebrafish, by approximately 40% over the control group after 72 h of treatment. This study indicated that Sp-LECin is a promising antibacterial agent with the potential to be used against devastating global pathogen infections such as P. aeruginosa. [ABSTRACT FROM AUTHOR]

Cathelicidins are a group of host defense proteins that exhibit antibacterial, antiviral and immunomodulating properties, while they also promote wound healing and participate in cell proliferation and angiogenesis. Cathelicidins have been detected in many animal species, including cattle, in which 8 genes coding for these proteins were identified. Moreover, in cows these proteins are involved in the response to mastitis. The aim of this study was to estimate associations between polymorphism in the CATHL2 gene in the 807 G>A position and some milk production traits and reproductive traits. The study included 539 Polish Holstein-Friesian Black-and-White cows. The ACRS and PCR-RFLP method was used to identify genotypes. The CATHL2/MseI frequencies were as follows: GG – 0.644, GA – 0.311 and AA – 0.045. In this study, no statistically significant associations between CATHL2 genotypes and the analyzed traits were found; however, a tendency to maintain a relationship of genotypes with milk production traits and reproductive indicators is shown. [ABSTRACT FROM AUTHOR]

Oxidation is an integral part of aerobic processes of life. It involves the transfer of electrons or hydrogen via a chemical reaction from a substance to an oxidizing agent leading to the production of free radicals. These free radicals which are highly reactive in turn initiate a chain of reactions that lead to cellular damage. The etiology of plethora diseases has been linked to the generation of free radicals beyond the body's antioxidant capacity, leading to oxidative stress. Consequently, the focus of research has tilted toward plants which provide natural products rich in antioxidants capable of scavenging and distrupting the harmful effects of these free radicals. A large group of compounds produced by plants referred to as phytochemicals possessing high antioxidant properties have been seen to be helpful in tackling numerous diseases. This review covered the antioxidant potential of some plants with medicinal properties beneficial to people, industries, and health institutions who desire their potential benefits. A total of two hundred and fifty plants from the following families; Asteraceae, Combretaceae, Euphorbiaceae, Fabaceae, Lamiaceae, Moraceae and Malvaceae were reviewed. These plants exert important biological properties, such as anti-inflammatory, antioxidant, immunomodulatory, anticancer, and antimicrobial properties, among others. [ABSTRACT FROM AUTHOR]

The potato- Phytophthora infestans system was used as a model to investigate how PR1 proteins protect plants against oomycete pathogens. Results showed that upon pathogen infection, PR1 proteins were induced, and secreted PR1 translocated into pathogen cells to target AMPK kinase complex, thus inhibiting vegetative growth and pathogenicity. Question marks and dotted lines represent scientific problems which need more detailed proofs. NPR1, nonexpressor of pathogenesis-related genes 1; TGA, TGACG-binding factor; SNF1, Sucrose non-fermenting 1; RxLR, the amino acid (Arg-x-Leu-Arg) of conserved motif in effector, where x is any amino acid. [Display omitted] • Upon infecting by P. infestans , StPR1 expression was induced in host and secretory StPR1 proteins translocated into pathogen. • The translocated PR1 proteins target AMPK complex in P. infestans , and impaired the AMPK activation to downstream targets. • StPR1 prevented ROS homeostasis and inhibited the expression of RxLR effector-encoding genes in P. infestans. During the arms race between plants and pathogens, pathogenesis-related proteins (PR) in host plants play a crucial role in disease resistance, especially PR1. PR1 constitute a secretory peptide family, and their role in plant defense has been widely demonstrated in both hosts and in vitro. However, the mechanisms by which they control host-pathogen interactions and the nature of their targets within the pathogen remain poorly understood. The present study was aimed to investigate the anti-oomycete activity of secretory PR1 proteins and elaborate their underlying mechanisms. This study was conducted in the potato- Phytophthora infestans pathosystem. After being induced by the pathogen infection, the cross-kingdom translocation of secretory PR1 was demonstrated by histochemical assays and western blot, and their targets in P. infestans were identified by yeast-two-hybrid assays, bimolecular fluorescence complementation assays, and co-immunoprecipitation assay. The results showed that the expression of secretory PR1-encoding genes was induced during pathogen infection, and the host could deliver PR1 into P. infestans to inhibit its vegetative growth and pathogenicity. The translocated secretory PR1 targeted the subunits of the AMPK kinase complex in P. infestans , thus affecting the AMPK-driven phosphorylation of downstream target proteins, preventing ROS homeostasis, and down-regulating the expression of RxLR effectors. The results provide novel insights into the molecular function of PR1 in protecting plants against pathogen infection, and uncover a potential target for preventing pre- and post-harvest late blight. [ABSTRACT FROM AUTHOR]

Novel ecological antimicrobial approaches to dental caries focus on inhibiting cariogenic pathogens while enhancing the growth of health-associated commensal communities or suppressing cariogenic virulence without affecting the diversity of oral microbiota, which emphasize the crucial role of establishing a healthy microbiome in caries prevention. Considering that the acidified cariogenic microenvironment leads to the dysbiosis of microecology and demineralization of enamel, exploiting the acidic pH as a bioresponsive trigger to help materials and medications target cariogenic pathogens is a promising strategy to develop novel anticaries approaches. In this study, a pH-responsive antimicrobial peptide, LH12, was designed utilizing the pH-sensitivity of histidine, which showed higher cationicity and stronger interactions with bacterial cytomembranes at acidic pH. Streptococcus mutans was used as the in vitro caries model to evaluate the inhibitory effects of LH12 on the cariogenic properties, such as biofilm formation, biofilm morphology, acidurance, acidogenicity, and exopolysaccharides synthesis. The dual-species model of Streptococcus mutans and Streptococcus gordonii was established in vitro to evaluate the regulation effects of LH12 on the mixed species microbial community containing both cariogenic bacteria and commensal bacteria. LH12 suppressed the cariogenic properties and regulated the bacterial composition to a healthier condition through a dual-functional mechanism. Firstly, LH12-targeted cariogenic pathogens in response to the acidified microenvironment and suppressed the cariogenic virulence by inhibiting the expression of multiple virulence genes and two-component signal transduction systems. Additionally, LH12 elevated H2O2 production of the commensal bacteria and subsequently improved the ecological competitiveness of the commensals. The dual-functional mechanism made LH12 a potential bioresponsive approach to caries management. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine whether Newcastle disease/infectious bronchitis (ND/IB) vaccination and yeast product diet supplementation modulate the expression of innate immune molecules in the proventriculus and ileum of broiler chicks. One-day-old male broiler chicks were divided into four groups (V-Y- (control), V-Y+, V+Y-, and V+Y+ groups, where V and Y represent vaccination and yeast product supplementation, respectively). Chicks in the V+Y- and V+Y+ groups were immunized with the live ND/IB vaccine, whereas chicks in the V-Y- and V-Y+ groups were not. Chicks in the V-Y+ and V+Y+ groups received feed containing yeast products from day 4, whereas chicks in the V-Y- and V+Y- groups did not. The proventriculus and ileum were collected on day 7 to analyze the expression of seven Toll-like receptors (TLRs) and Dectin-1. In the proventriculus, compared with those of the V-Y- control group, the TLR7 and TLR21 expression levels were higher in the V+Y- group; however, there were no differences in the expression levels of any TLR or Dectin-1 in the ileum. There were also no differences in the expression of avian ß-defensins and cathelicidin-1 in the proventriculus and ileum between the control and treatment groups. The expression of granzyme in cytotoxic cells and interleukin (IL)-1B was upregulated by ND/IB vaccination in the proventriculus. Supplementation with yeast products upregulated only granzyme expression in the ileum and downregulated IL-6 expression in the proventriculus in chicks immunized with the ND/IB vaccine. Thus, we concluded that ND/IB vaccination is effective at enhancing the innate immune system in the proventriculus of chicks, at least until day 7 post-hatching, whereas the effects of diet supplementation with yeast products may be limited, at least under the present study conditions. [ABSTRACT FROM AUTHOR]

Background: Differentiating between febrile lower urinary tract infection (LUTI) and acute pyelonephritis (APN) is crucial for prompt clinical management. We investigated whether the high mobility group box-1 (HMGB1) could be a useful biomarker in differentiating between LUTI or APN. Methods: We enrolled seventy-four pediatric patients with suspected LUTI/APN, according to the positive or negative renal scintigraphy (DMSA) scan. If the first DMSA findings were abnormal, a second DMSA was performed after six months. Voiding cystourethrography ruled out vesicoureteral reflux (VUR). Results: Higher serum (s) HMGB1 levels characterized the APN group when compared to LUTI patients (13.3 (11.8–14.3) versus 5.9 (5.2–6.8) ng/mL, p: 0.02), whereas there were no differences according to urine (u) HMGB1 values. sHMGB1 correlated with C-reactive protein (CRP) levels (β = 0.47; p: 0.02). Receiver operating characteristic curves identified the best diagnostic profile for detecting APN. sHMGB1 area under the curve was different from CRP (p: 0.01) and white blood cells (p: 0.003). After multivariate analyses, VUR (HR:4.81) and sHMGB1 (HR 1.16; p: 0.006) were independently associated with the risk of renal scarring development. Conclusions: sHMGB1 could represent a marker to differentiate APN from LUTI. Measurement of sHMGB1 could select children for early intervention or long-term follow-up. [ABSTRACT FROM AUTHOR]

Background: Antimicrobial peptide LL-37 is produced in response to active vitamin D and produces immunomodulatory effects and inhibits Mycobacterium tuberculosis replication in vitro. To date, no such clinical studies have been conducted to show relationship between 25hydroxyvitamin D and drug resistant tuberculosis patients in Pakistan. Objective: This study was conducted to find the association between insufficiencies of vitamin D with Cathelicidin LL-37 in drug-resistant tuberculosis patients and compare them with the control group. Methodology: Newly diagnosed drug-resistant TB patients and healthy controls ages 15-50 years old (mean 27.17, SD ± 10.37 years) were enrolled. Plasma LL-37 and serum 25 (OH) D levels were measured by ELISA technique in 46 patients and 94 controls. Results: There was a significant difference (p-value <.001) in the level of Vitamin D in both case and control group. Vitamin D insufficiency prevalence was 57.8% and 42.2% with the mean baseline concentrations of 34.39ng/mL (SD ± 15.28) and 39.41ng/mL (SD ± 18.28) in cases and control respectively. In the mean serum concentrations 52.95ng/mL (SD ± 19.67) and 39.00ng/mL (SD ± 18.02) of LL-37 in cases and control respectively, there was a significant difference of P-value <.001 was found. However, concentrations of vitamin D did not associate with serum LL-37 concentrations (p-value>0.05). Conclusion: Cathelicidine LL-37 is a potential biomarker of TB disease. However, the relationship between vitamin D & LL-37 requires further studies in TB patients. [ABSTRACT FROM AUTHOR]

The antimicrobial resistance crisis calls for the discovery and production of new antimicrobials. Host defense peptides (HDPs) are small proteins with potent antibacterial and immunomodulatory activities that are attractive for translational applications, with several already under clinical trials. Traditionally, antimicrobial peptides have been produced by chemical synthesis, which is expensive and requires the use of toxic reagents, hindering the large-scale development of HDPs. Alternatively, HDPs can be produced recombinantly to overcome these limitations. Their antimicrobial nature, however, can make them toxic to the hosts of recombinant production. In this review we explore the different strategies that are used to fine-tune their activities, bioengineer them, and optimize the recombinant production of HDPs in various cell factories. [ABSTRACT FROM AUTHOR]

Peptides are short sequences of proteins consisting of two or more amino acids that are linked by peptide bonds. Peptide-based designs and drug deliveries can offer several advantages, such as antioxidant, antimicrobial, antihypertensive activities, along with immunomodulatory and antithrombotic properties, with hormone or drug-like potential. Peptide-based therapeutic formulations are used as drug candidates for the treatment of various diseases. However, there are several concerns associated with the efficacy of peptides in pharmaceutical design and delivery, including rapid degradation, limited solubility, and poor permeability. The nanoformulation of peptides has been identified as a promising approach for improving the stability of peptides and providing metabolic stability and bioavailability. This article provides an overview of the advances in the development of peptides for drug design and formulation applications. It discusses various peptide nanoformulation approaches as well as recent developments in the in vitro and in vivo analyses of nanoformulated peptides for pharmaceutical applications. [ABSTRACT FROM AUTHOR]

Food preservation using biopreservative agents mainly microbial based metabolites have gained more attention in the modern food sector due to their broad spectrum anti-microbial efficacy with high biocompatibility. However, the effectiveness of these biopreservatives is highly dependent on suitable formulation which will enhance the desired efficacy without affecting the nutritional value of the foods. Polylysine-actinomycete derived anti-microbial metabolite is used as biopreservative agent in various food products. This review provides a valuable insight into the formulation of polylysine with nanotechnology principles for enhanced antimicrobial efficacy against food spoilage organisms. This review highlighted the diverse methods of polylysine nanoformulation preparation. Formulation of polylysine as functionalised nanomaterials can be prepared via green science or green technology principles was extensively studied in this review. This study also revealed the methods for the determination of anti-microbial assays and biocompatibility tests in vitro and in vivo biocompatibility tests. Future prospects of nanoformulated polylysine in bio preservation can be extended to safe processing of canned and ready-to-eat food products without affecting the nutritional value of the foods. [Display omitted] • Formulation of bio preservative agent poly lysine using nanotechnology principles is highlighted. • Nanoliposomal, nanoemulsion, nanoparticles conjugate, nanocomposite of polylysine preparation are featured. • Methods for determining respective nanoformulated poly lysine stability and biocompatibility are discussed. • This review suggests the possible utilisation of nanoformulated polylysine as an effective, safe bio preservative. [ABSTRACT FROM AUTHOR]

Host defense peptides (HDPs) are small molecules with broad-spectrum antimicrobial activities against infectious bacteria, viruses, and fungi. Increasing evidence suggests that HDPs can also indirectly protect hosts by modulating their immune responses. Due to these dual roles, HDPs have been considered one of the most promising antibiotic substitutes to improve growth performance, intestinal health, and immunity in farm animals. This review describes the antimicrobial and immunomodulatory roles of host defense peptides and their recent applications in animal production. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides are crucial components of innate immunity against microbial invasions. As a kind of antimicrobial peptides, bactericidal permeability-increasing protein (BPI)/lipopolysaccharide-binding protein (LBP) play vital roles in defending the host against gram-negative bacteria. In the current study, a novel BPI/LBP from Trachinotus ovatus (TroBPI/LBP) was characterized. The full length of TroBPI/LBP cDNA sequence is 1434 bp, which contained 477 amino acids. Multiple amino acid alignments of TroBPI/LBP shows 34.07%–84.49% identity with other fish BPI/LBP. Similar to other BPI/LBP, TroBPI/LBP also possesses an N-terminal signal peptide, a BPI/LBP/CETP N-terminal domain, and a BPI/LBP/CETP C-terminal domain. In vitro , the recombinant protein of TroBPI/LBP showed effective bacterial depression activity and binding activity to gram-negative bacteria. In vivo , TroBPI/LBP was constitutively expressed in tested tissues, and the highest expression level was in liver. Following Vibrio alginolyticus stimulation, the mRNA expression of TroBPI/LBP was significantly upregulated in immune-related tissues, and peaked at 12 h post-infection, which confirmed that TroBPI/LBP was highly sensitive to V. alginolyticus stimuli. Furthermore, functional analyses showed that the overexpression of TroBPI/LBP could enhance the ability of fish to against V. alginolyticus infection, and the knockdown of TroBPI/LBP significantly diminished bacterial clearance capacity post-infection. Therefore, these results suggest that TroBPI/LBP may play an important role in host defense against bacterial infection. • A TroBPI/LBP was cloned from golden pompano Trachinotus ovatus. • TroBPI/LBP exhibited antibacterial and bacterial binding activities. • TroBPI/LBP expression was up-regulated after V. alginolyticus infection. • TroBPI/LBP overexpression improved clearance against V. alginolyticus. [ABSTRACT FROM AUTHOR]

In this study, seven transcripts representing a novel antimicrobial peptide (AMP) family with structural features similar to those of arthropod defensins were identified from Mytilus coruscus. These novel defensins from the Mytilus AMP family were named myticofensins. To explore the possible immune-related functions of these myticofensins, we examined their expression profiles in different tissues and larval stages, as well as in three immune-related tissues under the threat of different microbes. Our data revealed that the seven myticofensins had relatively high expression levels in immune-related tissues. Most myticofensins were undetectable, or had low expression levels, in different larval mussel stages. Additionally, in vivo microbial challenges significantly increased the expression levels of myticofensins in M. coruscus hemocytes, gills, and digestive glands, showing different immune response patterns under challenges from different microbes. Our data indicates that different myticofensins may have different immune functions in different tissues. Furthermore, peptide sequences corresponding to the beta-hairpin, alpha-helix, and N-terminal loop of myticofensin were synthesized and the antimicrobial activities of these peptide fragments were tested. Our data confirms the diversity of defensins in Mytilus and reports the complex regulation of these defensins in the mussel immune response to different microbes in immune-related tissues. The immune system of Mytilus has been studied for years as they are a species with strong environmental adaptations. Our data can be regarded as a step forward in the study of the adaptation of Mytilus spp. to an evolving microbial world. • Seven novel antimicrobial peptides named myticofensin were identified from M. coruscus. • The expression profiles of the myticofensin genes were determined. • Myticofensins showed different responses to different microbial challenges in vivo. • The possible active sites were verified for several myticofensins. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides are an ancient and innate system of host defence against a wide range of microbial assailants. Mechanistically, unstructured peptides undergo a secondary structure transition into amphipathic α‐helices, upon contact with membrane surfaces. This leads to peptide binding and removal of the membrane components in a detergent‐like manner or via self‐organisation into trans‐membrane pores (either barrel‐stave or toroidal pore) thereby destroying the microbe. Self‐assembly of antimicrobial peptides into oligomers and ultimately amyloid has been mostly examined in parallel, however recent findings link diseases, such as Alzheimer's disease as an aberrant activity of a protective neuropeptide with antimicrobial activity. These self‐assembled oligomers can also interact with membranes. Here, we review those antimicrobial peptides reported to self‐assemble into amyloid, where supported by structural evidence. We consider their membrane activities as antimicrobial peptides and present evidence of consistent self‐assembly patterns across major evolutionary groups. Trends are apparent across these groups, supporting the mounting data that self‐assembly of antimicrobial peptides into amyloid should be considered as synergistic to the antimicrobial peptide response. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that mouse cathelicidin-related antimicrobial peptide (CRAMP) and its human homologue leucine leucine-37 (LL-37) play critical roles in innate immune responses. Here, we studied the role of mouse CRAMP in bacterial endotoxin lipopolysaccharide (LPS)-induced neuroinflammation. CRAMP peptide treatment significantly inhibited LPS-mediated inflammatory activation of glial cells in culture. In the animal model of LPS-induced neuroinflammation, CRAMP expression was highly induced in multiple cell types, such as astrocytes, microglia, and neurons. Injection of exogenous CRAMP peptide significantly inhibited inflammatory cytokine expression and the reactivity of glial cells in the mouse brain following intraperitoneal or intracerebroventricular LPS administration. Altogether, results of the study suggest that CRAMP plays an important part in containment of LPS-induced neuroinflammatory responses, and that CRAMP can be exploited for the development of targeted therapies for neuroinflammatory conditions associated with bacterial infection. [ABSTRACT FROM AUTHOR]

Objective: Researchers are studying the use of antimicrobial peptides as functional biomaterials to prevent and treat dental caries. This study aims to investigate the global research interest in antimicrobial peptides for caries management. Methods: Two independent investigators systematically searched with keywords ('Caries' OR 'Dental caries') AND ('Antimicrobial peptide' OR 'AMP' OR 'Statherin' OR 'Histatin' OR 'Defensin' OR 'Cathelicidin') on Web of Science, PubMed and Scopus. They removed duplicate publications and screened the titles and abstracts to identify relevant publications. The included publications were summarized and classified as laboratory studies, clinical trials or reviews. The citation count and citation density of the three publication types were compared using a one-way analysis of variance. The publications' bibliometric data were analyzed using the Bibliometrix program. Results: This study included 163 publications with 115 laboratory studies (71%), 29 clinical trials (18%) and 19 reviews (11%). The number of publications per year have increased steadily since 2002. The citation densities (mean ± SD) of laboratory study publications (3.67 ± 2.73) and clinical trial publications (2.63 ± 1.85) were less than that of review articles (5.79 ± 1.27) (p = 0.002). The three publication types had no significant difference in citation count (p = 0.54). Most publications (79%, 129/163) reported the development of a novel antimicrobial peptide. China (52/163, 32%) and the US (29/163, 18%) contributed to 50% (81/163) of the publications. Conclusion: This bibliometric analysis identified an increasing trend in global interest in antimicrobial peptides for caries management since 2002. The main research topic was the development of novel antimicrobial peptides. Most publications were laboratory studies, as were the three publications with the highest citation counts. Laboratory studies had high citation counts, whereas reviews had high citation density. [ABSTRACT FROM AUTHOR]

Cationic antimicrobial peptides (CAMPs) have gained attention as promising antimicrobial therapeutics causing lower or no bacterial resistance. Considerable achievements have been made in designing new CAMPs that are highly active as antimicrobials. However, there is a lack of research on their interaction with biologically important proteins. This study focused on CAMPs' effects on myeloperoxidase (MPO), an enzyme which is microbicidal and concomitantly damaging to host biomolecules and cells due to its ability to produce reactive oxygen and halogen species (ROS/RHS). Four CAMPs designed by us were employed. MPO catalytic activity was assessed by an absorbance spectra analysis and by measuring enzymatic activity using Amplex Red- and Celestine Blue B-based assays. The peptide Hm-AMP2 accelerated MPO turnover. Pept_1545 and Hm-AMP8 inhibited both the MPO chlorinating and peroxidase activities, with components of different inhibition types. Hm-AMP8 was a stronger inhibitor. Its Ki towards H2O2 and Cl– was 0.3–0.4 μM vs. 11–20 μM for pept_1545. Peptide tyrosine and cysteine residues were involved in the mechanisms of the observed effects. The results propose a possible dual role of CAMPs as both antimicrobial agents and agents that downregulate MPO activation, and suggest CAMPs as prototypes for the development of antioxidant compounds to prevent MPO-mediated ROS/RHS overproduction. [ABSTRACT FROM AUTHOR]

High oxygen concentrations are often required to treat newborn infants with respiratory distress but have adverse effects, such as increased oxidative stress and ferroptosis and impaired alveolarization. Cathelicidins are a family of antimicrobial peptides that exhibit antioxidant activity, and they can reduce hyperoxia-induced oxidative stress. This study evaluated the effects of cathelicidin treatment on lung ferroptosis and alveolarization in hyperoxia-exposed newborn rats. Sprague Dawley rat pups were either reared in room air (RA) or hyperoxia (85% O2) and then randomly given cathelicidin (8 mg/kg) in 0.05 mL of normal saline (NS), or NS was administered intraperitoneally on postnatal days from 1–6. The four groups obtained were as follows: RA + NS, RA + cathelicidin, O2 + NS, and O2 + cathelicidin. On postnatal day 7, lungs were harvested for histological, biochemical, and Western blot analyses. The rats nurtured in hyperoxia and treated with NS exhibited significantly lower body weight and cathelicidin expression, higher Fe2+, malondialdehyde, iron deposition, mitochondrial damage (TOMM20), and interleukin-1β (IL-1β), and significantly lower glutathione, glutathione peroxidase 4, and radial alveolar count (RAC) compared to the rats kept in RA and treated with NS or cathelicidin. Cathelicidin treatment mitigated hyperoxia-induced lung injury, as demonstrated by higher RAC and lower TOMM20 and IL-1β levels. The attenuation of lung injury was accompanied by decreased ferroptosis. These findings indicated that cathelicidin mitigated hyperoxia-induced lung injury in the rats, most likely by inhibiting ferroptosis. [ABSTRACT FROM AUTHOR]

The coding region for the sortase A (SrtA) of Staphylococcus aureus was fused at the N-terminus of LfcinB. The SrtA-LfcinB fusion protein in E. coli C43(DE3) was expressed with the expected sizes of 21 kDa and 38 kDa by pET21b-SrtA-LfcinB and pET32-1SrtA-LfcinB constructs, respectively. Increased levels of the TrxA-His-SrtA-SrtA-LfcinB fusion protein were detected by the pET32-3SrtA-LfcinB construct having three expression cassettes. LfcinB is released from the expressed SrtA-LfcinB protein by SrtA self-cleavage which is induced in the presence of Ca2+. The antibacterial activity was detected after SrtA-mediated cleavage of LfcinB. Furthermore, to reduce the antimicrobial peptide toxicity to the E. coli host, the human interferon-γ (hIFN-γ) sequences were mutated into a negatively charged mIFc2 protein (7 kDa), which was co-expressed with LfcinB in an insoluble form. The yield of LfcinB was elevated while changing the gene order of LfcinB and mIFc2 (pET21b-fLfcinB-bmIFc2). Furthermore, increased levels of LfcinB were detected using the pET21b-(fLfcinB-bmIFc2)2 construct. To increase the dissolution rate of inclusion bodies, inclusion bodies treated with different temperatures and pH and resuspended in different volumes of 50 mM Tris-HCl were assayed. Our results reveal that heat-treated LfcinB/mIFc2 inclusion bodies at 90 °C, pH 10, and 16X resuspended volumes have the best resolubilization rate. This work suggests that the mIFc2 co-expression system shows higher efficiency for LfcinB production than the SrtA fusion system. The expressed LfcinB from the mIFc2 co-expression system exhibits excellent broad-spectrum antibacterial activities against thirteen Gram-negative and ten Gram-positive bacteria species with a range of minimum inhibitory concentrations (MIC) between 37–150 ug/mL. [ABSTRACT FROM AUTHOR]