Search Results (252)

Cathelicidins are a family of antimicrobial peptides (AMPs) with broad-spectrum activity and immunomodulatory functions. Among them, the only human cathelicidin LL-37 has garnered significant interest due to its potent antimicrobial, antiviral, antifungal, antiparasitic, and antitumor properties. However, the clinical application of LL-37 is hindered by several limitations, including low proteolytic stability, cytotoxicity, and high production costs. To overcome these challenges, a wide range of design strategies have been employed to modify LL-37 and improve its therapeutic potential. LL-37-based analogs represent promising candidates for the development of next-generation antimicrobial and immunomodulatory therapies. Despite significant progress, further research is required to optimize peptide design, ensure cost-effective production, and validate long-term safety and efficacy. Advances in computational modeling, high-throughput screening, and nanotechnology will play an important role in the translation of modified cathelicidins into clinical practice. This review summarizes key strategies of chemical and structural modifications of LL-37 aimed at enhancing its functional properties. Particular attention is given to truncated and retro-analogs, which preserve or improve biological activity while exhibiting reduced toxicity and increased proteolytic resistance. Furthermore, we highlight the use of nanoscale delivery systems, which facilitate targeted delivery, prolong peptide half-life, and mitigate cytotoxic effects. Full article

Background/Objectives: Infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa are steadily increasing, thus the discovery and development of new and effective agents are needed. Antimicrobial peptides (AMPs) are a heterogeneous group of innate defense system peptides with broad antimicrobial activity. In this study, 17 AMPs were tested, identifying CAP-18, a cathelicidin-based compound, as the most active. CAP-18 was optimized by synthesizing structural derivatives, which were selected for further studies based on their activity against a collection of MDR and colistin-resistant P. aeruginosa strains. Methods: AMPs collection was initially tested against different P. aeruginosa strains, identifying CAP-18 as the most active. CAP-18 derivatives were synthetized and assessed by the Minimum Inhibitory Concentration (MIC), time-kill kinetics, cytotoxicity against human cell lines, hemolytic activity, and therapeutic index (IC₅₀/MIC₉₀). The mechanism of action was assessed by Transmission Electron Microscopy (TEM), and in vivo efficacy was determined through a murine skin infection model. Results: CAP-18 and D-CAP-18 had a MIC₉₀ of 4 and 2 μg/mL, respectively, whereas CAP-18₃₁ and D-CAP-18₃₁ presented MIC₉₀ values of 16 mg/L. The shorter derivatives of CAP-18 showed a lower activity. Time-kill curves revealed a fast bactericidal effect. These derivatives showed low toxicity against different human cell lines and low hemolysis, resulting in a wide therapeutic index (IC₅₀/MIC₉₀), with D-CAP-18 having the best therapeutic index (137.4). TEM provided insight into the mechanism of action, revealing bacterial membrane damage. In vivo studies of both CAP-18 and D-CAP-18 showed good activity with a 3 log decrease compared to the infected control group. Conclusions: Among the investigated four peptides, D-CAP-18 is the most promising candidate to treat skin infections caused by MDR P. aeruginosa since it shows potent activity both in vitro and in vivo, and a high therapeutic index. Full article

Osteoarthritis (OA) is the most prevalent form of joint arthritis, frequently associated with aging, mechanical wear, and inflammation. Our previous work demonstrated that cathelicidin-related antimicrobial peptide (Cramp) is upregulated in mouse OA cartilage, and that transient knockdown (KD) of Cramp in cultured chondrocytes decreases IL-1β-induced expression of matrix-degrading enzymes. The aim of this study was to determine the in vivo role of Cramp in OA pathogenesis using whole-body Cramp knockout (KO) mice. Normal skeletal development and growth plate morphology were assessed in E18.5d embryos and 2-week-old mice, respectively. Expression profiles of catabolic and anabolic genes were analyzed in primary chondrocytes derived from Cramp KO mice. OA in mouse knee joints was induced using intra-articular monosodium iodoacetate (MIA) injections or surgical destabilization of the medial meniscus (DMM). We observed that Cramp loss does not impact normal skeletal development. In contrast to our expectations, complete Cramp deficiency in chondrocytes failed to decrease catabolic gene expression upon IL-1β stimulation. Instead, genetic deletion of Cramp significantly worsened OA cartilage degradation in both MIA- and DMM-induced models. The detrimental phenotype observed in Cramp-deficient mice results from enhanced chondrocyte apoptosis. Therefore, even minimal Cramp expression appears essential for maintaining catabolic balance and preventing chondrocyte apoptosis in OA cartilage. Collectively, our data indicate that Cramp may exert multifaceted effects on OA pathogenesis by modulating catabolic pathways and apoptosis. Full article

The objectives of the present work were as follows: (i) the detection of cathelicidin biomolecules in the milk of individual goats during the early stages of mastitis and their potential use for the diagnosis of mastitis at its early stage and (ii) the evaluation of the presence of cathelicidin proteins in the bulk-tank milk from goat and sheep farms. In an experimental study, after inoculation of Staphylococcus simulans into a mammary gland of goats, bacteriological and cytological examinations of milk samples, as well as proteomics examinations [two-dimensional gel electrophoresis analysis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF MS) analysis] were performed sequentially, from 4 to 48 h post-challenge. Cathelicidin-1 and cathelicidin-2 were detected consistently in milk samples obtained throughout the study, and spot optical densities obtained from PDQuest v.8.0 were recorded. Associations were calculated between the presence of mastitis in a mammary gland at a given timepoint and the detection of cathelicidin proteins in the respective milk sample. All inoculated mammary glands developed mastitis, confirmed by the consistent bacterial isolation from milk samples and the increased somatic cell content therein. Spot optical density of cathelicidin proteins was higher than in samples from contralateral mammary glands. There was a significant association between the presence of mastitis in a mammary gland and the detection of cathelicidin biomolecules in the respective milk sample; the overall accuracy was 81.8% (95% confidence interval: 70.4–90.2%). In a field investigation, the presence of cathelicidin proteins was evaluated in the bulk-tank milk of 32 dairy goat and 57 dairy sheep farms. In this part of the work, no cathelicidin proteins were detected in any bulk-tank milk sample of goat, 0.0% (95% confidence interval: 0.0–10.7%), or sheep, 0.0% (95% confidence interval: 0.0–6.3%), farms. Full article

Dendrobium, a prominent genus in the Orchidaceae family, has generated significant research attention due to its demonstrated biological potential, particularly its notable anti-inflammatory and antioxidant activities. In this study, two fractions of fermented Dendrobium officinale polysaccharides (FDOPs) were successfully isolated through a multi-stage purification strategy including gradient ethanol precipitation, gel column chromatography, and ion exchange chromatography with Lactobacillus reuteri CCFM863. Structural characterization revealed that both Dendrobium officinale polysaccharide fractions consisted of (1→4)-β-D-Manp, (1→4)-β-D-Glcp, and (1→4)-α-D-Glcp residues. The anti-inflammatory efficacy and keratinocyte-protective potential of FDOPs (FDOP-1A and FDOP-2A) were investigated by using lipopolysaccharide (LPS)-induced RAW264.7 and HaCaT cells models, which showed significant inhibitions on the inflammatory factors of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), and interleukin-1 beta (IL-1β); recovered levels of filaggrin (FLG), aquaporin 3 (AQP3), transient receptor potential vanilloid 4 (TRPV4), cathelicidin antimicrobial peptide (CAMP)/LL-37, and adiponectin (ADIPOQ); and the reduced protein expression of the TLR4/IκB-α/NF-κB/NLRP3 pathway. Notably, the FDOPs exhibited a remarkable reactive oxygen species (ROS) scavenging capacity, demonstrating superior antioxidant activity. Therefore, FDOPs show dual anti-inflammatory and antioxidant properties, making them suitable as active ingredients for modulating epidermal inflammation and promoting skin barrier repair. Full article

Infections with the protozoan Neospora caninum cause abortion in cattle, likely due to the parasite’s replication and excessive inflammation in the placenta. Cathelicidins are host defense peptides known for their antimicrobial and immunomodulatory functions, but their role in N. caninum infections remains elusive. Using bone marrow-derived macrophages (BMDMs) isolated from mice expressing (wild-type, Camp^+/+) and lacking (Camp^−/−) cathelicidins, we investigated the role of endogenous cathelicidin in infections with N. caninum. We show that Camp^−/− macrophages primed with lipopolysaccharide (LPS) had an increased number of intracellular N. caninum tachyzoites, and these macrophages released higher amounts of IL-1β and lactate dehydrogenase (LDH), a marker of cytotoxicity. These findings indicate that cathelicidins contribute to intracellular N. caninum control and inflammation by limiting the activation of the inflammasome, particularly under LPS-induced conditions. This insight reveals the immunomodulatory role of cathelicidins in controlling N. caninum-associated pathologies. Full article

Herpes simplex virus type 1 (HSV-1) is a globally prevalent pathogen that can infect a variety of animal species as well as humans. However, existing antiviral therapies are constrained in their capacity to effectively target viral latency and prevent recurrent infections. Antimicrobial peptides (AMPs), particularly cathelicidins, as part of innate immune system have demonstrated broad-spectrum efficacy against viral pathogens. In this study, four peptides derived from Elephas maximus cathelicidin EM were designed and optimized (EM-1 to EM-4). We identified low toxicity peptide derivatives through hemolytic and cytotoxicity assays, quantified their anti-HSV-1 activity by determining IC₅₀. Antiviral mechanisms were investigated using RT-qPCR and antiviral efficacy was ultimately validated in C57BL/6J mice through viral load quantification in brain, lung, and heart tissues. Our findings revealed that EM-1 significantly inhibited HSV-1 replication in U251 cells. In a murine footpad inoculation model, EM-1 administration substantially reduced viral loads and alleviated inflammatory responses. Histological assessment demonstrated that EM-1 treatment mitigated HSV-1 induced tissue damage in infected mice. We also found that EM-1 exerted its antiviral effects by upregulating the expression of interferon-gamma and its downstream genes, such as ISG15 and MX1. These findings indicated that EM-1 is a dual function peptide that inhibits replication of HSV-1 as well as enhances host antiviral immunity. Collectively, this study highlights the therapeutic potential of elephant cathelicidin derived peptides in antiviral development. Full article

Regulating the innate immune response against infections, particularly drug-resistant bacteria, is a key focus in anti-infection therapy. Cathelicidins, found in vertebrates, are crucial for pathogen resistance. Few studies have explored gecko cathelicidins’ anti-infection properties. Recently, five new cathelicidins (Gj-CATH1-5) were identified in Gekko japonicus. The peptide Gj-CATH5, from G. japonicus, shows promise against Pseudomonas aeruginosa through various mechanisms. This study examined Gj-CATH5’s protective effects using in vitro and in vivo models, finding that it significantly reduced bacterial load in a mouse infection model when administered before or shortly after infection. Flow cytometry and the plate counting method showed that Gj-CATH5 boosts neutrophil and macrophage activity, enhancing chemotaxis, phagocytosis, and bactericidal functions. Gj-CATH5 increases ROS production, MPO activity, and NET formation, aiding pathogen clearance. Its amphipathic α-helical structure supports broad-spectrum bactericidal activity (MBC: 4–8 μg/mL) against Gram-negative and antibiotic-resistant bacteria. Gj-CATH5 is minimally cytotoxic (<8% hemolysis at 200 μg/mL) and preserves cell viability at therapeutic levels. These results highlight Gj-CATH5’s dual role in pathogen elimination and immune modulation, offering a promising approach to combat multidrug-resistant infections while reducing inflammation. This study enhances the understanding of reptilian cathelicidins and lays the groundwork for peptide-based immune therapies against difficult bacterial infections. Full article

Clostridium perfringens is a major cause of necrotizing enteritis in chickens. This study aimed to investigate the effects of zinc oxide quantum dots (ZnO-QDs) on growth performance, redox status, and gut microbiota in broilers challenged with C. perfringens. A total of 320 1-day-old chicks were divided into five groups: negative control (NC) without treatment; positive control (PC) infected with C. perfringens; and the other three groups (40, 80, and 120 Zn) were given ZnO-QDs at doses of 40, 80, and 120 mg/kg, respectively, under C. perfringens infection, respectively. The results show that, compared to the NC group, the PC group exhibited negative effects on growth performance, intestinal morphology, and antioxidant status in broilers. However, compared to the PC group, 120 mg Zn increased (p < 0.05) the body weight of broilers at 21 days, while 40 mg Zn reduced (p < 0.05) serum diamine oxidase activity. The intestinal macroscopic evaluation showed that the PC group had the highest lesion scores, whereas the 120 mg Zn group exhibited the lowest lesion score. Meanwhile, compared to the PC group, the 40 mg Zn group had higher (p < 0.05) CAT and GPX activities and a lower (p < 0.05) MDA concentration. Moreover, the 40 mg Zn group up-regulated (p < 0.05) the gene expression of Cathelicidin-1, IL-10, Claudin-1, and MLCK in the jejunum. Furthermore, the 120 mg Zn group increased (p < 0.05) the abundance of Blautia, Parasutterella, and Lachnospiraceae FCS020 in the cecum. In conclusion, ZnO-QDs exerted a beneficial effect on improving growth performance and overall health in broilers under C. perfringens infection, potentially by regulating redox balance and gut microbiota. Full article

Breast milk is vital for infant survival, protecting against infections and strengthening the immune system. In addition to nutrients, breast milk contains beneficial microorganisms, antimicrobial peptides and proteins (APPs), including lactoferrin and lysozyme, and peptides such as defensins and cathelicidins that destroy harmful bacteria and regulate the neonatal immune response. Breast milk also promotes the growth of beneficial gut bacteria (Bacteroidaceae and Bifidobacteriaceae) while reducing harmful pathogens, fostering a healthy gut microbiome, and supporting long-term infant health. Traditionally, research on antimicrobial proteins and milk microbiota has been conducted in isolation. However, at the molecular level, these components do not function independently; they interact synergistically, influencing immunomodulation, inflammation, and the composition of the gut microbiome. Therefore, this review aims to provide an overview of the discovery and identification of APPs in breast milk, the dynamic relationship between the breast milk microbiota, and the potentiation of artificial feeding with supplemented formulas when breastfeeding is impossible, benefits on newborn immune systems, and even the benefits to breast tissue. Full article

Background: The genetic modification of mesenchymal stromal/stem cells (MSCs) to express antimicrobial peptides may provide a promising strategy for developing advanced cell-based therapies for bacterial infections, including those caused or complicated by antibiotic-resistant bacteria. We have previously demonstrated that genetically modified Wharton’s jelly-derived MSCs expressing an antimicrobial peptide SE-33 (WJ-MSC-SE33) effectively reduce bacterial load, inflammation, and mortality in a mouse model of Staphylococcus aureus-induced pneumonia compared with native WJ-MSCs. The present study aimed to evaluate the pharmacokinetics and tissue distribution of the SE-33 peptide expressed by WJ-MSC-SE33 following administration to animals. Methods: WJ-MSC-SE33 were administered to C57BL/6 mice at therapeutic and excess doses. The biodistribution and pharmacokinetics of the SE-33 peptide were analyzed in serum, lungs, liver, and spleen using chromatographic methods after single and repeated administrations. Results: The SE-33 peptide exhibited dose-dependent pharmacokinetics. The highest levels of SE-33 peptide were detected in the liver and lungs, with persistence in tissues for up to 48 h at medium and high doses of administered WJ-MSC-SE33. A repeated administration of WJ-MSC-SE33 increased SE-33 levels in target organs. Conclusions: The SE-33 peptide expressed by genetically modified WJ-MSCs demonstrated predictable pharmacokinetics and effective biodistribution. These findings, together with the previously established safety profile of WJ-MSC-SE33, support its potential as a promising cell-based therapy for bacterial infections, particularly those associated with antibiotic resistance. Full article

Urinary tract infections (UTI) are among the most frequent bacterial infections in children, representing a significant cause of morbidity with potential long-term complications, including renal scarring and chronic kidney disease. This review explores the multifaceted roles of vitamins A, D, E, and C in the prevention and management of pediatric UTI. Vitamin A supports mucosal barrier integrity and immune modulation, reducing pathogen adhesion and colonization. Vitamin C exhibits antioxidant and antimicrobial properties, acidifying urine to inhibit bacterial growth and enhancing the efficacy of antibiotics. Vitamin D strengthens innate immunity by promoting antimicrobial peptide production, such as cathelicidins, and improves epithelial barrier function, while vitamin E mitigates oxidative stress, reducing renal inflammation and tissue damage. The interplay between oxidative stress, immune response, and nutritional factors is emphasized, highlighting the potential of these vitamins to restore antioxidant balance and prevent renal injury. Complementary strategies, including probiotics and phytotherapeutic agents, further enhance therapeutic outcomes by addressing microbiome diversity and providing additional antimicrobial effects. While these approaches show promise in mitigating UTI recurrence and reducing dependence on antibiotics, evidence gaps remain regarding optimal dosing, long-term outcomes, and their integration into pediatric care. By adopting a holistic approach incorporating vitamin supplementation and conventional therapies, clinicians can achieve improved clinical outcomes, support antibiotic stewardship, and reduce the risk of renal complications in children with UTI. Full article

Candidiasis belongs to common fungal infections and is usually mild and self-limiting. However, in patients with immunodeficiencies, it can transform into invasive infections with high mortality. Long-term antifungal treatment can lead to the emergence of resistance. The problem is further complicated by the development of fungal biofilm resistant to conventional antimicrobials. Due to a limited choice of available antifungals, the development of novel active agents, such as antimicrobial peptides (AMPs), is highly desirable. Human cathelicidin LL-37 is an intensively studied AMP with a confirmed broad spectrum of antimicrobial activities. Due to the relatively high costs of production, the design of shorter analogs of LL-37 has been recommended. In this study, we synthesized a KR12 amide, KRIVQRIKDFLR-NH₂, and its 24 derivatives obtained by substitution with fatty acids. The compounds were tested for their antifungal potential. They exhibited activity against the Candida albicans, C. glabrata, C. tropicalis and C. lipolytica. Five compounds: C₁₀-KR12-NH₂, C₁₂-KR12-NH₂, C₁₄-KR12-NH₂, 2-butyloctanoic acid-KR12-NH₂, and 4-phenylbenzoic acid-KR12-NH₂ were highly active against planktonic cells. C₁₄-KR12-NH₂ demonstrated also activity against C. albicans biofilm cultured on polystyrene for 24, 48 and 72 h. Lipidation has proven to be an effective strategy for improving microbiological activity of the KR12-NH₂ peptide. Full article

Isothermal titration calorimetry (ITC), circular dichroism (CD) spectroscopy, and molecular dynamics simulations were applied to describe interactions between lipopeptides and decavanadate ions ([V₁₀O₂₈]⁶⁻). The selected lipopeptides are conjugates of the amide of the KR12 peptide, the smallest antimicrobial peptide derived from human cathelicidin LL-37, with lauric acid (C12-KR12) and myristic acid (C14-KR12). The smaller sizes of C12-KR12 and C14-KR12 compared to proteins allow for the rigorous characterization of their non-covalent interactions with highly negatively charged [V₁₀O₂₈]⁶⁻ ions. The stoichiometry of the resulting decavanadate–peptide complexes and the thermodynamic parameters (ΔG, ΔH, and TΔS) of the interactions were determined. The ITC results, supported by the MD simulation, showed that the binding of cationic lipopeptides for decavanadate is rather non-specific and is driven by enthalpic contributions resulting from electrostatic interactions between the positively charged residues of the peptides and the anionic decavanadate. Furthermore, the influence of temperature and the interactions with decavanadate ions on the stability of the α-helical structure of the lipopeptides were assessed based on CD spectra. Under the experimental conditions (50 mM sodium cacodylate buffer, pH 5), the peptides adopt an α-helical conformation, with C14-KR12 showing greater thermal stability. The interactions with vanadium species disrupt the α-helical structure and reduce its thermal stability. Full article

Various species of fungi can be detected in the environment and within the human body, many of which may become pathogenic under specific conditions, leading to various forms of fungal infections. Antimicrobial peptides (AMPs) are evolutionarily ancient components of the immune response that are quickly induced in response to infections with many pathogens in almost all tissues. There is a wide range of AMP classes in humans, many of which exhibit broad-spectrum antimicrobial function. This review provides a comprehensive overview of the mechanisms of action of AMPs, their distribution in the human body, and their antifungal activity against a range of both common and rare clinical fungal pathogens. It also discusses the current research status of promising novel antifungal strategies, highlighting the challenges that must be overcome in the development of these therapies. The hope is that antimicrobial peptides, as a class of antimicrobial agents, will soon progress through large-scale clinical trials and be implemented in clinical practice, offering new treatment options for patients suffering from infections. Full article