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The emergence and re-emergence of multi-drug-resistant (MDR) infectious diseases have once again posed a significant global health challenge, largely attributed to the development of bacterial resistance to conventional anti-microbial treatments. To mitigate the risk of drug resistance globally, both antibiotics and immunotherapy are essential. Antimicrobial peptides (AMPs), also referred to as host defense peptides (HDPs), present a promising therapeutic alternative for treating drug-resistant infections due to their various mechanisms of action, which encompass antimicrobial and immunomodulatory effects. Many eukaryotic organisms produce HDPs as a defense mechanism, for example Purothionin from Triticum aestivum plant, Defensins, Cathelicidins, and Histatins from humans and many such peptides are currently the focus of research because of their antibacterial, antiviral and anti-fungicidal properties. This article offers a comprehensive review of the immunomodulatory activities of HDPs derived from eukaryotic organisms including humans, plants, birds, amphibians, reptiles, and marine species along with their mechanisms of action and therapeutic benefits. [ABSTRACT FROM AUTHOR]

Introduction: Maternal nutrition during pregnancy critically influences offspring development and immune function. One-carbon metabolites (OCM) are epigenetic modifiers that may modulate antimicrobial peptide (AMP) expression, which is vital for innate immunity. This study investigated the effects of maternal nutrient restriction and OCM supplementation on mRNA expression of AMP in fetal and maternal lung, mammary gland, and small intestine of beef cattle. Methods: Twenty-nine crossbred Angus beef heifers were synchronized for estrus and artificially inseminated. They were assigned to one of four treatments in a 2 × 2 factorial design: nutritional plane [control (CON) vs. restricted (RES)] and OCM supplementation [without OCM (−OCM) or with OCM (+OCM)]. Heifers on the CON diet were fed to gain 0.45 kg/day, while RES heifers were fed to lose 0.23 kg/day. Treatments were applied from day 0 to 63 of gestation, after which all heifers were fed a common diet to gain 0.45 kg/day until day 161 of gestation, when samples were collected. Quantitative RT-qPCR was used to assess mRNA expression of AMP. Results: Nutritional plane had no effect (p ≥ 0.24) on mRNA expression of AMP in either the fetus or dams. However, the mRNA expression of cathelicidin5 (CATHL5 ; p = 0.07) and bovine neutrophil β-defensin5 (BNBD5; p = 0.07) in the fetal lung and mammary gland, respectively, was lower in the +OCM groups compared to the −OCM groups. In the maternal small intestine, the expression of enteric β-defensin (EBD) was lower (p = 0.01) in the +OCM groups compared to the −OCM groups. Additionally, in the maternal lung, there was a tendency (p = 0.06) for an interaction in CATHL5 mRNA expression, with the RES + OCM group showing greater expression compared to the CON + OCM (p = 0.07) and RES − OCM (p = 0.08) groups. Discussion: Our findings suggest that while restricted maternal nutrition did not affect mRNA expression of AMP, OCM supplementation modulated AMP expression in both fetal and maternal tissues. Further research is needed to elucidate the mechanisms underlying OCM's impact on AMP expression. [ABSTRACT FROM AUTHOR]

Paclitaxel is a widely used chemotherapeutic agent for treating various solid tumors. However, resulting neuropathic pain, often a lifelong side effect of paclitaxel, can limit dosing and compromise optimal treatment. The choroid plexus, located in the brain ventricles, spreads peripheral inflammatory reactions into the brain. Our study is the first to analyze the effects of paclitaxel on inflammatory alterations in the choroid plexus. We hypothesized that the choroid plexus could respond directly to paclitaxel and simultaneously be indirectly altered via circulating damage-associated molecular patterns (DAMPs) produced by paclitaxel application. Using immunohistochemical and Western blot analysis, we examined the levels of toll-like receptor 9 (TLR9) and formyl peptide receptor 2 (FPR2), along with the pro-inflammatory cytokines interleukin 6 (IL6) and tumor necrosis factor α (TNFα) in choroid plexus epithelial cells of male Wistar rats following paclitaxel treatment. Moreover, we utilized an in vitro model of choroid plexus epithelial cells, the Z310 cells, to investigate the changes in these cells in response to paclitaxel and DAMPs (CpG ODN). Our results demonstrate that paclitaxel increases TLR9 and FPR2 levels in the choroid plexus while inducing IL6 and TNFα upregulation in both acute and chronic manners. In vitro experiments further revealed that paclitaxel directly interacts with epithelial cells of the choroid plexus, leading to increased levels of TLR9, FPR2, IL6, and TNFα. Additionally, treatment of cells with CpG ODN, an agonist of TLR9, elicited upregulation of IL6 and TNFα. Our findings determined that paclitaxel influences the choroid plexus through both direct and indirect mechanisms, resulting in inflammatory profile alterations. Given the pivotal role of the choroid plexus in brain homeostasis, a compromised choroid plexus following chemotherapy may facilitate the spread of peripheral inflammation into the brain, consequently exacerbating the development of neuropathic pain. [ABSTRACT FROM AUTHOR]

Simple Summary: Many breast cancers do not respond to immune checkpoint inhibitor therapy, even when combined with the standard of care chemotherapy. Here, we sought to identify compounds that enhance T-cell-mediated toxicity in tumor cells using a high-throughput screen of known anti-cancer drugs. Beginning with a library of over 400 FDA-approved or investigational compounds, we chose four chemotherapy agents for detailed mechanistic follow-up. We describe potential immunostimulatory properties of paclitaxel, bleomycin sulfate, ispinisib, and etoposide. Ultimately, these studies provide insight into the potential immunostimulatory properties of the chosen follow-up compounds and suggest avenues for future investigations into optimizing chemotherapy partners to use with ICI. Background: Triple-negative breast cancers (TNBCs) typically have a greater immune cell infiltrate and are more likely to respond to immune checkpoint inhibition (ICI) than ER+ or HER2+ breast cancers. However, there is a crucial need to optimize combining chemotherapy strategies with ICI to enhance overall survival in TNBC. Methods: Therefore, we developed a high-throughput co-culture screening assay to identify compounds that enhance CD8+ T-cell-mediated tumor cell cytotoxicity. Over 400 FDA-approved compounds or agents under investigation for oncology indications were included in the screening library. Results: Four chemotherapy agents were chosen as priority hits for mechanistic follow-up due to their ability to enhance T-cell-mediated cytotoxicity at multiple doses and multiple time points: paclitaxel, bleomycin sulfate, ispinesib, and etoposide. Lead compounds affected the expression of MHCI, MHCII, and PD-L1 and induced markers of immunogenic cell death (extracellular ATP or HMGB1). Conclusions: Based on the ability to increase tumor cell susceptibility to T-cell-mediated cytotoxicity while minimizing T-cell toxicity, bleomycin was identified as the most promising lead candidate. Overall, the results of these studies provide mechanistic insight into potential new chemotherapy partners to enhance anti-PD-1 efficacy in TNBC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Modulated electro-hyperthermia combines the thermal and non-thermal effects of an applied electromagnetic field. This synergy allows for the selection of malignant cells with a minimal load on healthy cells. The modulated radiofrequency induces immunogenic effects, which promote the targeting of malignant cells in the system by activating the circulating tumour-specific killer cells, thereby acting as a vaccination against the tumour. Background: Modulated electro-hyperthermia (mEHT) is unique due to its combination of thermal and non-thermal effects. Method: This report summarizes the literature on the effects of mEHT observed in vitro and in vivo. Results: The thermal and electrical heterogeneity of tissues allows the radiofrequency signal to selectively target malignant tissue. The applied modulation appears to activate various apoptotic pathways, predominantly leading to immunogenic cell death (ICD). ICD promotes the release of damage-associated molecular patterns, potentially producing tumour-specific antigen-presenting cells. This abscopal-type effect may target distant metastases while treating the primary tumour locally. This immune memory effect is like vaccination mechanisms. Conclusions: The application of mEHT has the potential to expand from local to systemic disease, enabling the simultaneous treatment of micro- and macro-metastases. [ABSTRACT FROM AUTHOR]

Background: Despite the growing productivity of aquaculture, economic losses due to infectious diseases, environmental pollution, and human safety concerns related to antibiotic resistance are limiting its growth. Therefore, research is intensively focused on alternative strategies for controlling infectious diseases. Purpose: Antimicrobial peptides (AMPs) are short, usually cationic, amphipathic, germline-encoded endogenous peptides possessing molecular weight less than 13 kDa, which show an extended variety of different families of highly conserved peptides found widely throughout Nature, which play a crucial role in molecular and cellular host defense towards pathogens (bacteria, viruses, parasites, and fungi), tissue damage, and infection. Results: They emerge as a promising antibiotic alternative due to their unique and multidimensional properties, including their low potential for developing antimicrobial resistance, minimal cytotoxicity to mammalian cells, high selective cytotoxicity against bacteria, low residual flesh, and ability to modulate host immune responses. Also, their ability to act even in extremely high salt concentrations, makes them suitable potential targets for development as therapeutic antimicrobials. AMPs are induced by various elements, including dietary ingredients and specific molecules also known as pathogen-associated molecular patterns (PAMPs), which may activate downstream signals to initiate transcription of AMP genes. Fish are an excellent origin of the peptides, as they express all major AMP families, including defensins, cathelicidins, hepcidins, histone-derived peptides, and a fish-specific class, called piscidins. Given their increasing attention in research, this review investigates various fish AMPs, their biological activities, and mechanisms of action. Conclusion: The findings suggest that fish can serve as sources of unique peptides with a broad range of biological activities, thereby offering a novel class of antibiotics. [ABSTRACT FROM AUTHOR]

Today, Candida albicans is still the most common cause of both local and life-threatening systemic candidiasis. The spread of resistant fungal strains has resulted in an urgent need to search for new promising antimycotics. Here, we investigated the antifungal action of the tobacco defensin NaD1 against susceptible and resistant to azoles and echinocandins strains of C. albicans. We demonstrated that NaD1 was equally effective and fungicidal against all tested strains. The MIC and MFC values were 6.25 and 12.5 µM, respectively. We showed for the first time that NaD1 could act synergistically not only with caspofungin but also with human host defense antimicrobial peptides cathelicidin LL-37 and β-defensin-2 (HBD2) against susceptible and resistant fungal strains. Using flow cytometry, we demonstrated that NaD1 in combinations with LL-37 or HBD2 can reinforce each other by enhancing membrane disruption. Using the Caco-2 cell monolayer model, we demonstrated that NaD1 impaired the adhesion of C. albicans cells to the human epithelium. Moreover, NaD1 inhibited the formation of fungal biofilms in Sabouraud broth and less markedly in nutrient-rich RPMI-1640 medium, and enhanced the antibiofilm activity of caspofungin. Thus, we hypothesized that NaD1 might affect the development of candidiasis in vivo, including that caused by resistant fungal strains. [ABSTRACT FROM AUTHOR]

Background/Objectives: LL-37 is associated with metabolic syndrome (MetS), a constellation of risk factors comprising obesity, insulin resistance (IR), dyslipidemia, and hypertension, which elevates the risk of cardiovascular disease and type 2 diabetes. Methods: In this narrative review, we analyzed the literature focusing on recent developments in the relationship between cathelicidin and various components of MetS to provide a comprehensive overview. Results: Studies have shown that LL-37 is linked to inflammation in adipose tissue (AT) and the development of IR in obesity. Cathelicidin can enhance inflammation by activating pro-inflammatory genes, as well as modulate the inflammatory response. The mechanisms of IR include the activation of complex signaling pathways that induce inflammation and reduce insulin signaling in adipocytes. The activation of Toll-like receptors (TLRs) by cathelicidin stimulates the secretion of pro-inflammatory cytokines, contributing to the disruption of insulin function in adipose cells. Cathelicidin also influences lipid metabolism, with recent research showing a negative relationship between LL-37 levels and HDL cholesterol. Therefore, LL-37 is involved not only in the regulation of inflammation but also in lipid metabolism, potentially aggravating the cardiovascular complications associated with MetS. Conclusions: Cathelicidin plays a crucial role in regulating the balance between inflammatory and anti-inflammatory responses in MetS. Understanding the impact of LL-37 on these mechanisms may unveil novel approaches for addressing MetS and its associated complications. [ABSTRACT FROM AUTHOR]

Mastitis, often caused by bacterial infection, is an inflammatory condition affecting the mammary glands. The condition is particularly prevalent in dairy cattle. Current treatment of bovine mastitis heavily relies on the use of antibiotics. To identify alternative solutions to antibiotic use, we evaluated the antimicrobial activity of 14 cathelicidins reported from 10 animal species. In conjunction, we assessed two bacteriocins against the bovine-mastitis causative bacterial panel, consisting of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus cereus, Enterococcus faecalis, Streptococcus agalactiae, Streptococcus dysgalactiae, and Streptococcus equi. Among the antimicrobial peptides (AMPs), cc-CATH3, ML-CATH, and PD-CATH proved to be highly active (minimum inhibitory concentration of 2–41 μg/mL, 0.2–10.3 μM) against all bacterial strains in the panel and field isolates from milk, with elevated somatic cell counts (≥ 500,000 cells/mL). Of the AMPs tested in this study, ML-CATH presented the highest level of effectiveness in controlling mastitis-associated bacterial strains while also possessing minimal cytotoxicity and functional stability against pH change and a high salt condition. The results of in silico analyses on the biochemical features of 12 helical cathelicidins revealed that the charge of AMPs appears to be a major determinant in killing Gram-negative bacteria. Furthermore, we observed a unique motif, "N(n≥3)-P(n≥1)-N(n≥3)", from the sequences of PMAP-36, cc-CATH3, ML-CATH, and PD-CATH that exhibits potent antimicrobial activity against a broad spectrum of bacteria compared to others. Our findings support the proposition that AMPs could serve as effective antimicrobial alternatives to conventional antibiotics in treating complex animal diseases caused by microbial infection, such as bovine mastitis. [ABSTRACT FROM AUTHOR]

Cathelicidins, a category of critical host defense molecules in vertebrates, have been extensively studied for their bactericidal functions, but little is known about their non-bactericidal properties. Herein, a novel cathelicidin peptide (Atonp2) was identified from the plateau frog Nanorana ventripunctata. It did not exhibit bactericidal activity but showed significant therapeutic effects in chronic UVB radiation-induced mouse skin photoaging through inhibiting thickening, pyroptosis and inflammation in the epidermis, while inhibiting cellular senescence, collagen fibre breakage and type Ⅰ collagen reduction in the dermis. Further studies indicated that Atonp2 effectively scavenged UVB-induced intracellular ROS via tyrosines at positions 9 and 10, while activating the Keap1/Nrf2 pathway to protect epidermal keratinocytes against UVB radiation, which in turn indirectly reversed the senescence and collagen degradation of dermal fibroblasts, thereby ameliorating UVB-induced skin photoaging. As such, this study identified a non-bactericidal cathelicidin peptide with potent antioxidant functions, highlighting its potential to treat and prevent skin photoaging. [Display omitted] • A novel non-bactericidal cathelicidin peptide (Atonp2) was identified from the plateau frog Nanorana ventripunctata. • Atonp2 showed significant therapeutic effects in chronic UVB radiation-induced mouse skin photoaging. • Atonp2 can scavenge excess intracellular ROS and activate the Keap1/Nrf2 pathway in keratinocytes. • Atonp2 ameliorated fibroblast senescence by modulating the microenvironment of keratinocytes in photoaged skin of mice. [ABSTRACT FROM AUTHOR]

Abstract Mastitis, often caused by bacterial infection, is an inflammatory condition affecting the mammary glands. The condition is particularly prevalent in dairy cattle. Current treatment of bovine mastitis heavily relies on the use of antibiotics. To identify alternative solutions to antibiotic use, we evaluated the antimicrobial activity of 14 cathelicidins reported from 10 animal species. In conjunction, we assessed two bacteriocins against the bovine-mastitis causative bacterial panel, consisting of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus cereus, Enterococcus faecalis, Streptococcus agalactiae, Streptococcus dysgalactiae, and Streptococcus equi. Among the antimicrobial peptides (AMPs), cc-CATH3, ML-CATH, and PD-CATH proved to be highly active (minimum inhibitory concentration of 2–41 μg/mL, 0.2–10.3 μM) against all bacterial strains in the panel and field isolates from milk, with elevated somatic cell counts (≥ 500,000 cells/mL). Of the AMPs tested in this study, ML-CATH presented the highest level of effectiveness in controlling mastitis-associated bacterial strains while also possessing minimal cytotoxicity and functional stability against pH change and a high salt condition. The results of in silico analyses on the biochemical features of 12 helical cathelicidins revealed that the charge of AMPs appears to be a major determinant in killing Gram-negative bacteria. Furthermore, we observed a unique motif, “N(n≥3)-P(n≥1)-N(n≥3)”, from the sequences of PMAP-36, cc-CATH3, ML-CATH, and PD-CATH that exhibits potent antimicrobial activity against a broad spectrum of bacteria compared to others. Our findings support the proposition that AMPs could serve as effective antimicrobial alternatives to conventional antibiotics in treating complex animal diseases caused by microbial infection, such as bovine mastitis.

Cathelicidins (human LL-37 and rat CRAMP) are multifunctional peptides involved in various cardiovascular conditions. This review integrates the recent findings about the functional involvement of LL-37/CRAMP across atherosclerosis, acute coronary syndrome, myocardial infarction, heart failure, diabetic cardiomyopathy, and platelet aggregation/thrombosis. In atherosclerosis, LL-37 interacts with scavenger receptors to modulate lipid metabolism and binds with mitochondrial DNA and lipoproteins. In acute coronary syndrome, LL-37 influences T cell responses and mitigates calcification within atherosclerotic plaques. During myocardial infarction and ischaemia/reperfusion injury, LL-37/CRAMP exhibits dual roles: protecting against myocardial damage through the AKT and ERK1/2 signalling pathways, while exacerbating inflammation via TLR4 and NLRP3 inflammasome activation. In heart failure, LL-37/CRAMP attenuates hypertrophy and fibrosis via NF-κB inhibition and the activation of the IGFR1/PI3K/AKT and TLR9/AMPK pathways. Moreover, in diabetic cardiomyopathy, these peptides alleviate oxidative stress and fibrosis by inhibiting TGFβ/Smad and AMPK/mTOR signalling and provide anti-inflammatory effects by reducing NF-κB nuclear translocation and NLRP3 inflammasome formation. LL-37/CRAMP also modulates platelet aggregation and thrombosis through the FPR2 and GPVI receptors, impacting apoptosis, autophagy, and other critical cellular processes. This comprehensive overview underscores LL-37/CRAMP as a promising therapeutic target in cardiovascular diseases, necessitating further elucidation of its intricate signalling networks and biological effects for clinical translation.

Background: Acute respiratory distress syndrome (ARDS) has a high mortality rate if not diagnosed and treated promptly. Several markers could increase during ARDS, such as interleukin 6 (IL-6), high mobility group box-1 (HMGB-1), and neutrophil-to-lymphocyte ratio (NLR). This study aimed to determine the correlation between these markers and the severity of ARDS. Methods: This cross-sectional study was conducted at Dr. Wahidin Sudirohusodo General Hospital from January to April 2024. The population included in this study consisted of all patients treated in the Intensive Care Unit (ICU) and divided into two groups: ARDS and non-ARDS. IL-6, HMGB-1, and NLR were measured once during treatment. The severity assessment was conducted using the Berlin criteria (mild, moderate, severe) for ARDS patients. Results: A total of 30 patients were divided equally into two groups. Mean IL-6 levels were higher in ARDS patients (21.15±3.89) than in non-ARDS (12.56±3.08) with a significant difference (p=0.000). The mean HMGB-1 levels were also higher in ARDS (26.46±30.14) than in non- ARDS (9.37±4.23), with a significant difference (p=0.040). IL-6 (p=0.000) and HMGB-1 (p=0.026) were also significantly associated with ARDS severity. Conclusion: IL-6 and HMGB-1 are related to ARDS severity. [ABSTRACT FROM AUTHOR]

Despite their relatively short lifespan, neutrophils are tasked with counteracting pathogens through various functions, including phagocytosis, production of reactive oxygen species, neutrophil extracellular traps (NETs), and host defense peptides. Regarding the latter, small cationic cathelicidins present a conundrum in neutrophil function. Although primarily recognized as microbicides with an ability to provoke pores in microbial cell walls, the ability of cathelicidin to modulate key neutrophil functions is also of great importance, including the release of chemoattractants, cytokines, and reactive oxygen species, plus prolonging neutrophil lifespan. Cumulative evidence indicates a less recognized role of cathelicidin as an "immunomodulator"; however, this term is not always explicit, and its relevance in neutrophil responses during infection and inflammation is seldom discussed. This review compiles and discusses studies of how neutrophils use cathelicidin to respond to infections, while also acknowledging immunomodulatory aspects of cathelicidin through potential crosstalk between sources of the peptide. [ABSTRACT FROM AUTHOR]

The presented studies were aimed at determining the interactions in model membranes (Langmuir monolayers) created of phospholipids (PL) isolated from Legionella gormanii bacteria cultured with (PL + choline) or without (PL − choline) choline and to describe the impact of an antimicrobial peptide, human cathelicidin LL-37, on PL's monolayer behavior. The addition of choline to the growth medium influenced the mutual proportions of phospholipids extracted from L. gormanii. Four classes of phospholipids—phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), cardiolipin (CL), and their mixtures—were used to register compression isotherms with or without the LL-37 peptide in the subphase. Based on them the excess area ( A e ), excess ( Δ G e ), and total ( Δ G m ) Gibbs energy of mixing were determined. The thermodynamic analyses revealed that the PL − choline monolayer showed greater repulsive forces between molecules in comparison to the ideal system, while the PL + choline monolayer was characterized by greater attraction. The LL-37 peptide affected the strength of interactions between phospholipids' molecules and reduced the monolayers stability. Accordingly, the changes in interactions in the model membranes allowed us to determine the difference in their susceptibility to the LL-37 peptide depending on the choline supplementation of bacterial culture. [ABSTRACT FROM AUTHOR]

Amyloid peptides (AMYs) and antimicrobial peptides (AMPs) are considered as the two distinct families of peptides, characterized by their unique sequences, structures, biological functions, and specific pathological targets. However, accumulating evidence has revealed intriguing pathological connections between these peptide families in the context of microbial infection and neurodegenerative diseases. Some AMYs and AMPs share certain structural and functional characteristics, including the ability to self-assemble, the presence of β-sheet-rich structures, and membrane-disrupting mechanisms. These shared features enable AMYs to possess antimicrobial activity and AMPs to acquire amyloidogenic properties. Despite limited studies on AMYs–AMPs systems, the cross-seeding phenomenon between AMYs and AMPs has emerged as a crucial factor in the bidirectional communication between the pathogenesis of neurodegenerative diseases and host defense against microbial infections. In this review, we examine recent developments in the potential interplay between AMYs and AMPs, as well as their pathological implications for both infectious and neurodegenerative diseases. By discussing the current progress and challenges in this emerging field, this account aims to inspire further research and investments to enhance our understanding of the intricate molecular crosstalk between AMYs and AMPs. This knowledge holds great promise for the development of innovative therapies to combat both microbial infections and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

This review examines the potential applications of peptides in biotechnology, medicine, and pharmacy, while highlighting the important antibacterial and antiviral properties of peptides. Peptides and chemical peptide synthesis have become a field of study that is gaining great momentum today. Some of the main reasons for this are high specificity, biodegradability and versatility of peptides. Peptides also have some specific properties that make them attractive for pharmaceutical development. As a case study, it can be used to create peptides that can be used to replace or fix damaged proteins in the body by mimicking the action of naturally occurring proteins. Delivering drugs or other therapeutic agents to specific cells or tissues is another method that can help increase the effectiveness of treatment and reduce unwanted effects. Various types of antimicrobial peptides (AMPs), such as defensins and cathelicidins, and their anti‐infective properties are also discussed. Finally, peptides (melittin, lactoferricin, etc.) can be used to trigger an immune response against certain infections, such as COVID‐19 and Zika virus, by acting as vaccines. In our study, a comprehensive review was made on antiviral and AMPs, and especially peptides containing arginine and lysine were mentioned. The properties of these peptides, examples of these peptides and their developments in the pharmaceutical field are emphasized. [ABSTRACT FROM AUTHOR]

Cathelicidins (human LL-37 and rat CRAMP) are multifunctional peptides involved in various cardiovascular conditions. This review integrates the recent findings about the functional involvement of LL-37/CRAMP across atherosclerosis, acute coronary syndrome, myocardial infarction, heart failure, diabetic cardiomyopathy, and platelet aggregation/thrombosis. In atherosclerosis, LL-37 interacts with scavenger receptors to modulate lipid metabolism and binds with mitochondrial DNA and lipoproteins. In acute coronary syndrome, LL-37 influences T cell responses and mitigates calcification within atherosclerotic plaques. During myocardial infarction and ischaemia/reperfusion injury, LL-37/CRAMP exhibits dual roles: protecting against myocardial damage through the AKT and ERK1/2 signalling pathways, while exacerbating inflammation via TLR4 and NLRP3 inflammasome activation. In heart failure, LL-37/CRAMP attenuates hypertrophy and fibrosis via NF-κB inhibition and the activation of the IGFR1/PI3K/AKT and TLR9/AMPK pathways. Moreover, in diabetic cardiomyopathy, these peptides alleviate oxidative stress and fibrosis by inhibiting TGFβ/Smad and AMPK/mTOR signalling and provide anti-inflammatory effects by reducing NF-κB nuclear translocation and NLRP3 inflammasome formation. LL-37/CRAMP also modulates platelet aggregation and thrombosis through the FPR2 and GPVI receptors, impacting apoptosis, autophagy, and other critical cellular processes. This comprehensive overview underscores LL-37/CRAMP as a promising therapeutic target in cardiovascular diseases, necessitating further elucidation of its intricate signalling networks and biological effects for clinical translation. [ABSTRACT FROM AUTHOR]

Mass treatment with antibiotics at arrival has been the mainstay for bovine respiratory disease (BRD) control but there is an increase in antimicrobialresistant bacteria being shed from treated cattle. BRD is a disease complex that results from the interaction of viruses or bacteria and susceptible animals with inappropriate immunity. With bacteria being the only feasibly treatable agent and the emergence of antimicrobial resistance, decreased efficacy of commonly used antibiotics could threaten livestock health. There is a need for new antimicrobial alternatives that could be used to control disease. Naturally occurring antimicrobial peptides (AMP) have been proposed to address this need. Here we tested the effect of bovine myeloid antimicrobial peptide-28 (BMAP-28), a synthetic BMAP-28 analog Syn-1, and bactenecin 5 (Bac-5) on Mannheimia haemolytica (Mh) using a quantitative culture method and the broth microdilution method to determine minimum inhibitory and bactericidal concentrations (MIC and MBC). We also tested the antiviral effect of these AMP against bovine herpes-1 (BHV-1) and bovine respiratory syncytial virus (BRSV) using the Reed and Muench method to calculate the viral titers after treatment. We demonstrated that BMAP-28 and Syn-1 can inhibit Mh growth and BMAP-28 can inhibit replication of BHV-1 and BRSV. Moreover, we showed that BMAP28 and Bac-5 can be used together to inhibit Mh growth. When used alone, the MIC of BMAP-28 and Bac-5 was 64 and 128  μg/mL respectively, but when applied together, their MIC ranged from 0.25–16 for BMAP-28 and 8–64  μg/ mL for Bac-5, resulting in a decrease in concentration of up to 256 and 16- fold, respectively. The synergistic interaction between those peptides resulted in concentrations that could be well tolerated by cells. Our results demonstrate that bovine cathelicidins could be used as alternatives to antimicrobials against BRD pathogens. These findings introduce a path to discovering new antimicrobials and determining how these peptides could be tailored to improve cattle health. [ABSTRACT FROM AUTHOR]

Simple Summary: This review explores the potential of human defensins, particularly HBD-1, in combating colorectal cancer (CRC) initiation and progression. Highlighting the need for early detection and novel CRC therapies, it examines HBD-1's ability to inhibit the mTOR pathway, a key regulator of cell growth, positioning defensin-based treatments as a promising approach with evidence for suppressing cancer cell proliferation and tumor growth. Colorectal cancer (CRC) represents a significant global healthcare burden, with a particularly concerning rising incidence among younger adults. This trend may highlight potential links between diet, gut microbiome, and CRC risk. Novel therapeutic options have been increasingly based on the understanding of molecular mechanisms and pathways. The PI3K/AKT/mTOR pathway, a crucial cell growth regulator, offers a promising target for CRC therapy. mTOR, a key component within this pathway, controls cell growth, survival, and metabolism. Understanding the specific roles of defensins, particularly human β-Defensin 1 (HBD-1), in CRC is crucial. HBD-1 exhibits potent antimicrobial activity and may influence CRC development. Deciphering defensin expression patterns in CRC holds the promise of improved understanding of tumorigenesis, which may pave the way for improved diagnostics and therapies. This article reviews recent advances in understanding regarding how HBD-1 influences CRC initiation and progression, highlighting the molecular mechanisms by which it impacts CRC. Further, we describe the interaction between defensins and mTOR pathway in CRC. [ABSTRACT FROM AUTHOR]

Background: Fish skin mucus contains innate immune factors and acts as the first line of physical or chemical defense against pathogens. Objective: The primary aim of this study was to determine the antiviral activity of sea bream (SBr), rainbow trout (RT), and sea bass (SBa) fish skin mucus against herpes simplex virus (HSV)‐1. In addition, it was aimed to associate possible antiviral activity with antimicrobial peptides (AMPs) such as cathelicidin, hepcidin, galectin 2, and C10ORF99, whose levels were determined in the mucus. Methods: The antiviral activity and oxidative/antioxidant status of mucus against HSV‐1 virus was evaluated. In addition, AMPs, SOD, and CAT activities, and immunoglobulin M levels were also analyzed in mucus of fish. Results: Antiviral activity mucus of SBr, RT, and SBa against HSV‐1 were determined as 2−4, 2−5, and 2−2, respectively. The higher antiviral activity of SBr and RT mucus compared to the mucus of SBa can be associated with higher AMP levels in them. Conclusion: The skin mucus of SBr and RT may be nutritional supplement, adjuvant, and a new agent that can potentiate the effects of antimicrobial/antiviral agents. [ABSTRACT FROM AUTHOR]

IntroductionMaternal nutrition during pregnancy critically influences offspring development and immune function. One-carbon metabolites (OCM) are epigenetic modifiers that may modulate antimicrobial peptide (AMP) expression, which is vital for innate immunity. This study investigated the effects of maternal nutrient restriction and OCM supplementation on mRNA expression of AMP in fetal and maternal lung, mammary gland, and small intestine of beef cattle.MethodsTwenty-nine crossbred Angus beef heifers were synchronized for estrus and artificially inseminated. They were assigned to one of four treatments in a 2 × 2 factorial design: nutritional plane [control (CON) vs. restricted (RES)] and OCM supplementation [without OCM (−OCM) or with OCM (+OCM)]. Heifers on the CON diet were fed to gain 0.45 kg/day, while RES heifers were fed to lose 0.23 kg/day. Treatments were applied from day 0 to 63 of gestation, after which all heifers were fed a common diet to gain 0.45 kg/day until day 161 of gestation, when samples were collected. Quantitative RT-qPCR was used to assess mRNA expression of AMP.ResultsNutritional plane had no effect (p ≥ 0.24) on mRNA expression of AMP in either the fetus or dams. However, the mRNA expression of cathelicidin5 (CATHL5; p = 0.07) and bovine neutrophil β-defensin5 (BNBD5; p = 0.07) in the fetal lung and mammary gland, respectively, was lower in the +OCM groups compared to the −OCM groups. In the maternal small intestine, the expression of enteric β-defensin (EBD) was lower (p = 0.01) in the +OCM groups compared to the −OCM groups. Additionally, in the maternal lung, there was a tendency (p = 0.06) for an interaction in CATHL5 mRNA expression, with the RES + OCM group showing greater expression compared to the CON + OCM (p = 0.07) and RES − OCM (p = 0.08) groups.DiscussionOur findings suggest that while restricted maternal nutrition did not affect mRNA expression of AMP, OCM supplementation modulated AMP expression in both fetal and maternal tissues. Further research is needed to elucidate the mechanisms underlying OCM’s impact on AMP expression.

Porcine epidemic diarrhea virus (PEDV) is a harmful coronavirus infecting pigs, which is resulting in substantial financial losses in the global pig industry. The lack of effective vaccines or treatments underscores the pressing need for new antiviral strategies. Antimicrobial peptides (AMPs), specifically cathelicidins such as LL-37, have demonstrated promising activity against a range of viruses. This study aims to elucidate the antiviral mechanisms of cathelicidins by examining their inhibitory capabilities against PEDV in vitro. Four pig-derived antimicrobial peptides (PMAP-36, PMAP-23, PR-39, and PG-1), together with chicken-derived CATH-B1 and human-derived LL-37 were analyzed for their anti-PEDV activity. Flow cytometry and fluorescent microscopy confirmed that LL-37 and CATH-B1 had strong inhibitory effects at non-toxic concentrations of 5 and 10 µM, significantly reducing GFP-PEDV infection of Vero cells both in co- and pre-incubation setups. In contrast, none of the porcine peptides exhibited any inhibitory effects, even at higher doses. Fluorogenic LL-37 was shown to enter VERO cells, indicative of a possible immunomodulatory antiviral mode of action. However, transmission electron microscopy clearly indicated that both LL-37 and CATH-B1 affected virus morphology and caused aggregation of viral particles, showing that peptide-virus interaction caused reduced virus infectivity. In conclusion, this analysis highlights the potential of LL-37 and CATH-B1 as inhibitors against PEDV, suggesting promising directions for innovative therapeutic antiviral strategies.

To reduce food spoilage and deterioration caused by microbial contamination, antimicrobial peptides (AMPs) have gradually gained attention as a biological preservative. Odorranain-C1 is an α-helical cationic antimicrobial peptide extracted from the skin of frogs with broad-spectrum antimicrobial activity. In this study, we achieved the expression of Odorranain-C1 in Pichia pastoris (P. pastoris) (also known as Komagataella phaffii) by employing DNA recombination technology. The recombinant Odorranain-C1 showed broad-spectrum antibacterial activity and displayed a minimum inhibitory concentration within the range of 8–12 μg.mL-1. Meanwhile, Odorranain-C1 exhibited superior stability and lower hemolytic activity. Mechanistically, Odorranain-C1 disrupted the bacterial membrane's integrity, ultimately causing membrane rupture and subsequent cell death. In tilapia fillets preservation, Odorranain-C1 inhibited the total colony growth and pH variations, while also reducing the production of total volatile basic nitrogen (TVB-N) and thiobarbituric acid (TBA). In conclusion, these studies demonstrated the efficient recombinant expression of Odorranain-C1 in P. pastoris , highlighting its promising utilization in food preservation. • Odorranain-C1 was successfully expressed in Pichia pastoris for the first time. • Odorranain-C1 showed broad-spectrum antibacterial activity and good stability. • The mechanism of Odorranain-C1 is to destroy the integrity of bacterial membranes. • Odorranain-C1 can be used to keep tilapia fillets fresh and prolong their shelf life. [ABSTRACT FROM AUTHOR]

The alarming increase in antimicrobial resistance in the last decades has prompted the search for alternatives to control infectious diseases. Antimicrobial peptides (AMPs) represent a heterogeneous class of molecules with ample antibacterial, antiviral, and antifungal effects. They can be found in many organisms, including all classes of vertebrates, providing a valuable source of new antimicrobial agents. The unique properties of AMPs make it harder for microbes develop resistance, while their immunomodulatory properties and target diversity reinforce their translational use in multiple diseases, from autoimmune disorders to different types of cancer. The latest years have witnessed a vast number of studies evaluating the use of AMPs in therapy, with many progressing to clinical trials. The present review explores the recent developments in the medicinal properties of cathelicidins, a vast family of AMPs with potent antimicrobial and immunomodulatory effects. Cathelicidins from several organisms have been tested in disease models of viral and bacterial infections, inflammatory diseases, and tumors, with encouraging results. Combining nanomaterials with active, natural antimicrobial peptides, including LL-37 and synthetic analogs like ceragenins, leads to the creation of innovative nanoagents with significant clinical promise. However, there are still important limitations, such as the toxicity of many cathelicidins to healthy host cells and low stability in vivo. The recent advances in nanomaterials and synthetic biology may help overcome the current limitations, enabling the use of cathelicidins in future therapeutics. Furthermore, a better understanding of the mechanisms of cathelicidin action in vivo and their synergy with other host molecules will contribute to the development of safer, highly effective therapies. [ABSTRACT FROM AUTHOR]

Objectives To quantify associations of serum alarmins with risk of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Methods Using serum collected at enrolment, three alarmins (IL-33, thymic stromal lymphopoietin [TSLP] and IL-25) were measured in a multicentre prospective RA cohort. ILD was classified using systematic medical record review. Cross-sectional associations of log-transformed (IL-33, TSLP) or quartile (IL-25) values with RA-ILD at enrolment (prevalent RA-ILD) were examined using logistic regression, while associations with incident RA-ILD developing after enrolment were examined using Cox proportional hazards. Covariates in multivariate models included age, sex, race, smoking status, RA disease activity score and anti-cyclic citrullinated antibody positivity. Results Of 2835 study participants, 115 participants (4.1%) had prevalent RA-ILD at baseline and an additional 146 (5.1%) developed incident ILD. There were no associations between serum alarmin concentrations and prevalent ILD in unadjusted or adjusted logistic regression models. In contrast, there was a significant inverse association between IL-33 concentration and the risk of developing incident RA-ILD in unadjusted (hazard ratio [HR] 0.73 per log-fold increase; 95% CI: 0.57, 0.95; P  = 0.018) and adjusted (HR 0.77; 95% CI: 0.59, 1.00; P  = 0.047) models. No significant associations of TSLP or IL-25 with incident ILD were observed. Conclusion In this study, we observed a significant inverse association between serum IL-33 concentration and the risk of developing incident RA-ILD, but no associations with prevalent ILD. Additional investigation is required to better understand the mechanisms driving this relationship and how serum alarmin IL-33 assessment might contribute to clinical risk stratification in patients with RA. [ABSTRACT FROM AUTHOR]

This article provides an overview of the development, structure and activity of various metal complexes with anti-cancer activity. Chemical researchers continue to work on the development and synthesis of new molecules that could act as anti-tumor drugs to achieve more favorable therapies. It is therefore important to have information about the various chemotherapeutic substances and their mode of action. This review focuses on metallodrugs that contain a metal as a key structural fragment, with cisplatin paving the way for their chemotherapeutic application. The text also looks at ruthenium complexes, including the therapeutic applications of phosphorescent ruthenium(II) complexes, emphasizing their dual role in therapy and diagnostics. In addition, the antitumor activities of titanium and gold derivatives, their side effects, and ongoing research to improve their efficacy and reduce adverse effects are discussed. Metallization of host defense peptides (HDPs) with various metal ions is also highlighted as a strategy that significantly enhances their anticancer activity by broadening their mechanisms of action. [ABSTRACT FROM AUTHOR]

Histone demethylase JMJD2D (also known as KDM4D) can specifically demethylate H3K9me2/3 to activate its target gene expression. Our previous study has demonstrated that JMJD2D can protect intestine from dextran sulfate sodium (DSS)-induced colitis by activating Hedgehog signaling; however, its involvement in host defense against enteric attaching and effacing bacterial infection remains unclear. The present study was aimed to investigate the role of JMJD2D in host defense against enteric bacteria and its underlying mechanisms. The enteric pathogen Citrobacter rodentium (C. rodentium) model was used to mimic clinical colonic infection. The responses of wild-type and JMJD2D-/- mice to oral infection of C. rodentium were investigated. Bone marrow chimeric mice were infected with C. rodentium. JMJD2D expression was knocked down in CMT93 cells by using small hairpin RNAs, and Western blot and real-time PCR assays were performed in these cells. The relationship between JMJD2D and STAT3 was studied by co-immunoprecipitation and chromatin immunoprecipitation. JMJD2D was significantly up-regulated in colonic epithelial cells of mice in response to Citrobacter rodentium infection. JMJD2D-/- mice displayed an impaired clearance of C. rodentium, more body weight loss, and more severe colonic tissue pathology compared with wild-type mice. JMJD2D-/- mice exhibited an impaired expression of IL-17F in the colonic epithelial cells, which restricts C. rodentium infection by inducing the expression of antimicrobial peptides. Accordingly, JMJD2D-/- mice showed a decreased expression of β-defensin-1, β-defensin-3, and β-defensin-4 in the colonic epithelial cells. Mechanistically, JMJD2D activated STAT3 signaling by inducing STAT3 phosphorylation and cooperated with STAT3 to induce IL-17F expression by interacting with STAT3 and been recruited to the IL-17F promoter to demethylate H3K9me3. Our study demonstrates that JMJD2D contributes to host defense against enteric bacteria through up-regulating IL-17F to induce β-defensin expression. Author summary: Our study aimed to unravel the role of JMJD2D, a histone demethylase also known as KDM4D, in the host's defense against enteric bacterial infections and explore the underlying mechanisms. While we had previously demonstrated JMJD2D's protective effect in DSS-induced colitis by activating Hedgehog signaling, its involvement in defending against enteric attaching and effacing bacterial infections remained unexplored. To address this, we employed a Citrobacter rodentium (C. rodentium) infection model to mimic colonic infections in a clinical context. In response to C. rodentium infection, there was a notable increase in JMJD2D expression within the colonic epithelial cells of mice. Our investigation compared the responses of wild-type mice with those lacking JMJD2D (JMJD2D-/-) following oral C. rodentium infection. Notably, JMJD2D-/- mice exhibited impaired C. rodentium clearance, greater body weight loss, and more severe colonic tissue damage compared to their wild-type counterparts. Subsequent analysis revealed that JMJD2D deficiency resulted in reduced IL-17F expression in colonic epithelial cells. IL-17F is a known regulator that restricts C. rodentium infection by promoting the expression of antimicrobial peptides. Consequently, JMJD2D-/- mice showed diminished expression of critical antimicrobial peptides, including β-defensin-1, β-defensin-3, and β-defensin-4, in their colonic epithelial cells. Mechanistically, we discovered that JMJD2D played a pivotal role in activating STAT3 signaling by enhancing STAT3 phosphorylation. Moreover, JMJD2D collaborated with STAT3 to induce IL-17F expression. This cooperation involved JMJD2D physically interacting with STAT3 and binding to the IL-17F promoter, where it demethylated H3K9me3. In summary, our research reveals that JMJD2D contributes significantly to the host's defense against enteric bacterial infections by up-regulating IL-17F, which in turn induces the expression of antimicrobial peptides such as β-defensins. Our findings provide valuable insights into the molecular mechanisms governing host defense against enteric bacterial infections, emphasizing the potential therapeutic relevance of targeting JMJD2D in such contexts. [ABSTRACT FROM AUTHOR]

The human cationic antimicrobial protein (hCAP) corresponding to the overlapping sequences of 151–162 of hCAP named KR-12 peptide is the smallest portion of the only type of human Cathelicidin, which has been shown to be modifiable into a more effective antimicrobial. In this study, an in silico analysis, supported by potentiometric titration and isothermal titration calorimetry techniques, was performed to identify potential Cu(II) binding sites of KR-12. The analysis of the presented data at the given theoretical level (GFN2-xTB/ALPB) revealed which peptide chain fragments are involved in the most favourable KR-12–Cu(II) binding mode. Based on a quantum chemical approach, the most favourable coordination modes of Cu(II) to peptides are proposed together with the discussion of the chemical nature of the interactions. The presented results demonstrated that KR-12 interacts with metal ions mostly via the main chain's oxygen atoms; however, the two types of amino acids that are expected to be vital for the interaction of Cu(II) are D (aspartic acid) and R29 (arginine). It was demonstrated that in order to explain the complexity of the interaction process in peptide–metal ion systems, the use of theoretical methods is sometimes necessary to explain the details of the experimental results and provide an in-depth understanding of these dynamic systems. [ABSTRACT FROM AUTHOR]

This document is a collection of references to scientific articles and studies on antimicrobial peptides (AMPs) and their potential applications. The articles cover a range of topics, including the development and modification of AMPs to enhance their stability and effectiveness, the use of AMPs in drug delivery systems, and the exploration of plant-derived AMPs for antimicrobial purposes. Other articles discuss the design principles and mechanisms of AMPs, the development of new antibiotics, and the potential of AMPs as antiviral agents. These references provide a comprehensive overview of current research in the field and can be a valuable resource for researchers studying AMPs and their applications. [Extracted from the article]

The emergence of drug-resistant bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), has increased the need to discover novel antimicrobial agents that are effective against these species. Here, we describe the identification and purification of the mutacin BHT-B-like gene locus and bacteriocin peptide from Streptococcus ursoris, which is closely related to Streptococcus ratti; hence, we named this bacteriocin ursoricin. Ursoricin is a cationic, chromosome-encoded peptide that has potent antimicrobial effects against Gram-positive pathogens, including MRSA and VRE, with minimum inhibitory concentrations in the micromolar range. Ursoricin also inhibits the biofilm formation of high biofilm-form ing S. aureus. Antibacterial activity was retained after treatment at 100°C for 60 min at a pH range of 3-9 and was partially reduced by treatment with proteinase K for 2 h (63% residual activity). The potent anti-MRSA, anti-VRE, and antibiofilm effects of ursoricin suggest that it is a possible candidate for the treatment of MRSA, VRE, and biofilm-associated infections. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) manifests clinically with chronic intestinal inflammation and microflora dysbiosis. Although biologics can effectively control inflammation, efficient delivery to the colon and colon epithelial cells remains challenging. Milk‐derived extracellular vesicles (EV) show promise as an oral delivery tool, however, the ability to load biologics into EV presents challenges to therapeutic applications. Here, we demonstrate that fusing cell‐penetrating peptide (TAT) to green fluorescent protein (GFP) enabled biologics loading into EV and protected against degradation in the gastrointestinal environment in vitro and in vivo after oral delivery. Oral administration of EV loaded with anti‐tumour necrosis factor‐α (TNF‐α) nanobody (VHHm3F) (EVVHH) via TAT significantly reduced tissue TNF‐α levels and alleviated pathologies in mice with acute UC, compared to VHH alone. In mice with chronic UC, simultaneously introducing VHH and an antimicrobial peptide LL37 into EV (EVLV), then administering orally improved intestinal barrier, inflammation and microbiota balance, resulted in relief of UC‐induced depression and anxiety. Collectively, we demonstrated that oral delivery of EVLV effectively alleviated UC in mice and TAT efficiently loaded biologics into EV to confer protection from degradation in the gastrointestinal tract. This therapeutic strategy is promising for UC and is a simple and generalizable approach towards drug‐loaded orally‐administrable EV treatment for other diseases. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of honokiol (HON) and the role of high-mobility group protein B1 (HMGB1) on the pathogenesis of severe acute pancreatitis (SAP). Methods: Thirty mice were numbered according to weight, and randomly divided into 5 groups using a random number table, including control, SAP, SAP and normal saline (SAP+NS), SAP and ethyl pyruvate (SAP+EP), or SAP+HON groups, 6 mice in each group. Samples of pancreas, intestine, and blood were collected 12 h after SAP model induction for examination of pathologic changes, immune function alterations by enzyme linked immunosorbent assay (ELISA), and Western blot. In vitro experiments, macrophages were divided into 5 groups, the control, lipopolysaccharide (LPS), LPS+DMSO (DMSO), LPS+anti-HMGB1 monoclonal antibody (mAb), and LPS+ HON groups. The tight connection level was determined by transmission electron microscopy and fluorescein isothiocyanate-labeled. The location and acetylation of HMGB1 were measured by Western blot. Finally, pyridone 6 and silencing signal transducer and activator of the transcription 1 (siSTAT1) combined with honokiol were added to determine whether the Janus kinase (JAK)/ STAT1 participated in the regulation of honokiol on HMGB1. The protein expression levels of HMGB1, JAK, and STAT1 were detected using Western blot. Results: Mice with SAP had inflammatory injury in the pancreas, bleeding of intestinal tissues, and cells with disrupted histology. Mice in the SAP+HON group had significantly fewer pathological changes. Mice with SAP also had significant increases in the serum levels of amylase, lipase, HMGB1, tumor necrosis factor- α, interleukin-6, diamine oxidase, endotoxin-1, and procalcitonin. Mice in the SAP+HON group did not show these abnormalities (P<0.01). Studies of Caco-2 cells indicated that LPS increased the levels of occludin and claudin-1 as well as tight junction permeability, decreased the levels of junctional adhesion molecule C, and elevated intercellular permeability (P<0.01). HON treatment blocked these effects. Studies of macrophages indicated that LPS led to low nuclear levels of HMGB1, however, HON treatment increased the nuclear level of HMGB1 (P<0.01). HON treatment also inhibited the expressions of JAK1, JAK2, and STAT1 (P<0.01) and increased the acetylation of HMGB1 (P<0.05). Conclusion: HON prevented intestinal barrier dysfunction in SAP by inhibiting HMGB1 acetylation and JAK/STAT1 pathway. [ABSTRACT FROM AUTHOR]

Avian colibacillosis (AC), caused by infection with Escherichia coli (E. coli), is a major threat to poultry health, food safety and public health, and results in high mortality and significant economic losses. Currently, new drugs are urgently needed to replace antibiotics due to the continuous emergence and increasing resistance of multidrug-resistant (MDR) strains of E. coli caused by the irrational use of antibiotics in agriculture and animal husbandry. In recent years, antimicrobial peptides (AMPs), which uniquely evolved to protect the host, have emerged as a leading alternative to antibiotics in clinical settings. CATH-2, a member of the antimicrobial cathelicidin peptide family, has been reported to have antibacterial activity. To enhance the antimicrobial potency and reduce the adverse effects on animals, we designed five novel AMPs, named C2-1, C2-2, C2-3, C2-4 and C2-5, based on chicken CATH-2, the secondary structures of these AMPs were consistently α-helical and had an altered net charge and hydrophobicity compared to those of the CATH-2 (1-15) sequences. Subsequently, the antimicrobial activities of CATH-2 (1-15) and five designed peptides against MDR E. coli were evaluated in vitro. Specifically, C2-2 showed excellent antimicrobial activity against either the ATCC standard strain or veterinary clinical isolates of MDR E. coli, with concentrations ranging from 2-8 mg/mL. Furthermore, C2-2 maintained its strong antibacterial efficacy under high temperature and saline conditions, demonstrating significant stability. Similarly, C2-2 retained a high level of safety with no significant hemolytic activity on chicken mature red blood cells or cytotoxicity on chicken kidney cells over the concentration range of 0-64 mg/mL. Moreover, the administration of C2-2 improved the survival rate and reduced the bacterial load in the heart, liver and spleen during MDR E. coli infection in chickens. Additionally, pathological damage to the heart, liver and intestine was prevented when MDR E. coli infected chickens were treated with C2-2. Together, our study showed that C2-2 may be a promising novel therapeutic agent for the treatment of MDR E. coli infections and AC. [ABSTRACT FROM AUTHOR]

With the increasing problem of antimicrobial drug resistance, the search for new antimicrobial agents has become a crucial task in the field of medicine. Antimicrobial peptides, as a class of naturally occurring antimicrobial agents, possess broad-spectrum antimicrobial activity and lower risk of resistance development. However, traditional screening methods for antimicrobial peptides are inefficient, necessitating the development of an efficient screening model. In this study, we aimed to develop an ensemble learning model for the identification of antimicrobial peptides, named E-CLEAP, based on the Multilayer Perceptron Classifier (MLP Classifier). By considering multiple features, including amino acid composition (AAC) and pseudo amino acid composition (PseAAC) of antimicrobial peptides, we aimed to improve the accuracy and generalization ability of the identification process. To validate the superiority of our model, we employed five-fold cross-validation and compared it with other commonly used methods for antimicrobial peptide identification. In the experimental results on an independent test set, E-CLEAP achieved accuracies of 97.33% and 84% for the AAC and PseAAC features, respectively. The results demonstrated that our model outperformed other methods in all evaluation metrics. The findings of this study highlight the potential of the E-CLEAP model in enhancing the efficiency and accuracy of antimicrobial peptide screening, which holds significant implications for drug development, disease treatment, and biotechnology advancement. Future research can further optimize the model by incorporating additional features and information, as well as validating its reliability on larger datasets and in real-world environments. The source code and all datasets are publicly available at https://github.com/Wangsicheng52/E-CLEAP. [ABSTRACT FROM AUTHOR]

Objective: Glioblastoma multiforme (GBM) is the most aggressive and fatal malignant primary brain tumor. The enhancement of the survival rate for glioma patients remains limited, even with the utilization of a combined treatment approach involving surgery, radiotherapy, and chemotherapy. This study was designed to assess the expression of IDH1, TP53, EGFR, Ki-67, GFAP, H3K27M, MGMT, VEGF, NOS, CD99, and ATRX in glioblastoma tissue from 11 patients. We investigated the anticancer impact and combined effects of cathelicidin (LL-37), protegrin-1 (PG-1), with chemotherapy—temozolomide (TMZ), doxorubicin (DOX), carboplatin (CB), cisplatin (CPL), and etoposide (ETO) in primary GBM cells. In addition, we examined the effect of LL-37, PG-1 on normal human fibroblasts and in the C6/Wistar rat intracerebral glioma model. Methods: For this study, 11 cases of glioblastoma were evaluated immunohistochemically for IDH1, TP53, EGFR, Ki-67, GFAP, H3K27M, MGMT, VEGF, NOS, CD99, and ATRX. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to study cells viability and to determine cytotoxic effects of LL-37, PG-1 and their combination with chemotherapy in primary GBM cells. Synergism or antagonism was determined using combination index (CI) method. Finally, we established C6 glioblastoma model in Wistar rats to investigate the antitumor activity. Results: Peptides showed a strong cytotoxic effect on primary GBM cells in the MTT test (IC50 2–16 and 1–32 μM) compared to chemotherapy. The dual-drug combinations of LL-37 + DOX, LL-37 + CB (CI 0.46–0.75) and PG-1 + DOX, PG-1 + CB, PG-1 + TMZ (CI 0.11–0.77), demonstrated a synergism in primary GBM cells. In rat C6 intracerebral GBM model, survival of rats in experimental group (66.75 ± 12.6 days) was prolonged compared with that in control cohort (26.2 ± 2.66 days, p = 0.0008). After LL-37 treatment, experimental group rats showed significantly lower tumor volumes (31.00 ± 8.8 mm3) and weight (49.4 ± 13.3 mg) compared with control group rats (153.8 ± 43.53 mg, p = 0.038; 82.50 ± 7.60 mm3, respectively). Conclusions: The combination of antimicrobial peptides and chemical drugs enhances the cytotoxicity of chemotherapy and exerts synergistic antitumor effects in primary GBM cells. Moreover, in vivo study provided the first evidence that LL-37 could effectively inhibit brain tumor growth in rat C6 intracerebral GBM model. These results suggested a significant strategy for proposing a promising therapy for the treatment of GBM. [ABSTRACT FROM AUTHOR]

Objective: Cathelicidin is a crucial antibacterial peptide that is produced in the urinary system and is induced by vitamin D. In order to distinguish between lower and upper urinary tract infections (UTIs), the association between cathelicidin levels and vitamin D levels was examined in this study. Material and Methods: We analyzed complete blood count, biochemistry profile, C reactive protein (CRP), 25 hydroxyvitamin D, serum cathelicidin levels of pre-treatment children aged 0-18 years who were diagnosed with a UTI in the Pediatric Emergency Room. Results: A total of 72 children (36 healthy and 36 patients) were included in the study. The mean age of the participants was 83.8±66.22 months, with 40 (56%) female and 32 (44%) male. Our patient group had higher white blood cell, neutrophil, and CRP levels than our control group (p=0.050). There was no significant difference in cathelicidin levels (5.7±3.7; 9.6±10.9; p=0.810) or vitamin D levels (23.3±9.5; 25.9±12.5; p=0.795) between patients with lower and upper UTI. We found a positive correlation between vitamin D and cathelicidin levels in the control group (r=0.346, p=0.030). There was no statistically significant difference in cathelicidin levels between patients with upper UTI and the control group (p=0.054). Conclusion: Although there was no significant relationship between vitamin D and cathelicidin levels in children with urinary tract infections, a weak but positive correlation exists between vitamin D and cathelisidin in healthy children. [ABSTRACT FROM AUTHOR]

For the last 30 years, Piscirickettsia salmonis has caused major economic losses to the aquaculture industry as the aetiological agent for the piscirickettsiosis disease. Replacing the current interventions, based on antibiotics, with natural alternatives (e.g., organic acids) represents a priority. With this study, we aimed to better understand their biological mechanism of action in an in vitro model of infection with salmon epithelial cells (CHSE-214). Our first observation revealed that at the sub-inhibitory concentration of 0.5%, the organic acid blend (Aq) protected epithelial cell integrity and significantly reduced P. salmonis invasion. The MIC was established at 1% Aq and the MBC at 2% against P. salmonis. The sub-inhibitory concentration significantly increased the expression of the antimicrobial peptides Cath2 and Hepcidin1, and stimulated the activity of the innate immune effector iNOS. The increase in iNOS activity also led to higher levels of nitric oxide (NO) being released in the extracellular space. The exposure of P. salmonis to the endogenous NO caused an increase in bacterial lipid peroxidation levels, a damaging effect which can ultimately reduce the pathogen's ability to attach or multiply intracellularly. We also demonstrate that the increased NO release by the host CHSE-214 cells is a consequence of direct exposure to Aq and is not dependent on P. salmonis infection. Additionally, the presence of Aq during P. salmonis infection of CHSE-214 cells significantly mitigated the expression of the pro-inflammatory cytokines IL-1β, IL-8, IL-12, and IFNγ. Taken together, these results indicate that, unlike antibiotics, natural antimicrobials can weaponize the iNOS pathway and secreted nitric oxide to reduce infection and inflammation in a Piscirickettsia salmonis in vitro model of infection. [ABSTRACT FROM AUTHOR]

Vitamin D is known to modulate human immune responses, and vitamin D deficiency is associated with increased susceptibility to infection. However, what constitutes sufficient levels or whether vitamin D is useful as an adjuvant therapeutic is debated, much in part because of inadequate elucidation of mechanisms underlying vitamin D's immune modulatory function. Cathelicidin antimicrobial peptide (CAMP) has potent broad-spectrum activity, and the CAMP gene is regulated in human innate immune cells by active 1,25(OH)2D3, a product of hydroxylation of inactive 25(OH)D3 by CYP27B1-hydroxylase. We developed a CRISPR/Cas9-edited human monocyte-macrophage cell line containing the mCherry fluorescent reporter gene at the 3' end of the endogenous CAMP gene. The High Throughput CAMP Assay (HiTCA) developed here is a novel tool for evaluating CAMP expression in a stable cell line that is scalable for a high-throughput workflow. Application of HiTCA to serum samples from a small number of human donors (n = 10) showed individual differences in CAMP induction that were not fully accounted for by the serum vitamin D metabolite status of the host. As such, HiTCA may be a useful tool that can advance our understanding of the human vitamin D-dependent antimicrobial response, which is being increasingly appreciated for its complexity.

This document discusses the importance of novel molecules in the treatment and diagnosis of diabetes mellitus, dyslipidemia, and cardiovascular disorders. It highlights the efficacy of new medications such as SGLT2 inhibitors, GLP-1 agonists, GIP agonists, and PCSK9 inhibitors in clinical trials. The document also emphasizes the potential of repurposing old drugs like metformin and statins to address new physiological pathways in these disorders. Various research studies are presented, including the role of miRNAs and biochemical markers as diagnostic tools, the interaction between inflammation and cardiovascular disease, and the potential applications of GLP-1 agonists and SGLT-2 inhibitors. The document concludes by emphasizing the need for continued research to discover new molecules and potential treatments for these chronic diseases. [Extracted from the article]

Background: Esculentin-1, initially discovered in the skin secretions of pool frogs (Pelophylax lessonae), has demonstrated broad-spectrum antimicrobial activity; however, its immunomodulatory properties have received little attention. Results: In the present study, esculentin-1 cDNA was identified by analysing the skin transcriptome of the dark-spotted frog (Pelophylax nigromaculatus). Esculentin-1 from this species (esculentin-1PN) encompasses a signal peptide, an acidic spacer peptide, and a mature peptide. Sequence alignments with other amphibian esculentins-1 demonstrated conservation of the peptide, and phylogenetic tree analysis revealed its closest genetic affinity to esculentin-1P, derived from the Fukien gold-striped pond frog (Pelophylax fukienensis). Esculentin-1PN transcripts were observed in various tissues, with the skin exhibiting the highest mRNA levels. Synthetic esculentin-1PN demonstrated antibacterial activity against various pathogens, and esculentin-1PN exhibited bactericidal activity by disrupting cell membrane integrity and hydrolyzing genomic DNA. Esculentin-1PN did not stimulate chemotaxis in RAW264.7, a murine leukemic monocyte/macrophage cell line. However, it amplified the respiratory burst and augmented the pro-inflammatory cytokine gene (TNF-α and IL-1β) expression in RAW264.7 cells. Conclusions: This novel finding highlights the immunomodulatory activity of esculentin-1PN on immune cells. [ABSTRACT FROM AUTHOR]

The oral organism Tannerella forsythia is auxotrophic for peptidoglycan amino sugar N‐acetylmuramic acid (MurNAc). It survives in the oral cavity by scavenging MurNAc‐ and MurNAc‐linked peptidoglycan fragments (muropeptides) secreted by co‐habiting bacteria such as Fusobacterium nucleatum with which it forms synergistic biofilms. Muropeptides, MurNAc‐l‐Ala‐d‐isoGln (MDP, muramyl dipeptide) and d‐γ‐glutamyl‐meso‐DAP (iE‐DAP dipeptide), are strong immunostimulatory molecules that activate nucleotide oligomerization domain (NOD)‐like innate immune receptors and induce the expression of inflammatory cytokines and antimicrobial peptides. In this study, we utilized an in vitro T. forsythia–F. nucleatum co‐culture model to determine if T. forsythia can selectively scavenge NOD ligands from the environment and impact NOD‐mediated inflammation. The results showed that NOD‐stimulatory molecules were secreted by F. nucleatum in the spent culture broth, which subsequently induced cytokine and antimicrobial peptide expression in oral epithelial cells. In the spent broth from T. forsythia–F. nucleatum co‐cultures, the NOD‐stimulatory activity was significantly reduced. These data indicated that F. nucleatum releases NOD2‐stimulatory muropeptides in the environment, and T. forsythia can effectively scavenge the muropeptides released by co‐habiting bacteria to dampen NOD‐mediated host responses. This proof‐of‐principle study demonstrated that peptidoglycan scavenging by T. forsythia can impact the innate immunity of oral epithelium by dampening NOD activation. [ABSTRACT FROM AUTHOR]

New antiviral agents are essential to improving treatment and control of SARS-CoV-2 infections that can lead to the disease COVID-19. Antimicrobial peptoids are sequence-specific oligo-N-substituted glycine peptidomimetics that emulate the structure and function of natural antimicrobial peptides but are resistant to proteases. We demonstrate antiviral activity of a new peptoid (TM9) against the coronavirus, murine hepatitis virus (MHV), as a closely related model for the structure and antiviral susceptibility profile of SARS-CoV-2. This peptoid mimics the human cathelicidin LL-37, which has also been shown to have antimicrobial and antiviral activity. In this study, TM9 was effective against three murine coronavirus strains, demonstrating that the therapeutic window is large enough to allow the use of TM9 for treatment. All three isolates of MHV generated infection in mice after 15 min of exposure by aerosol using the Madison aerosol chamber, and all three viral strains could be isolated from the lungs throughout the 5-day observation period post-infection, with the peak titers on day 2. MHV-A59 and MHV-A59-GFP were also isolated from the liver, heart, spleen, olfactory bulbs, and brain. These data demonstrate that MHV serves as a valuable natural murine model of coronavirus pathogenesis in multiple organs, including the brain. [ABSTRACT FROM AUTHOR]

Objective: Calprotectin (CLP), S100A6, and high mobility group nucleosome-binding protein 1 (HMGN1), known as alarmins, are involved in the pathogenesis of many tumors. In this study, we aimed to investigate the relationships of serum CLP, S100A6, and HMGN1 levels with the clinical and laboratory findings of patients with multiple myeloma (MM) and their roles in the pathogenesis of MM. Materials and Methods: We measured the serum CLP, S100A6, and HMGN1 levels of 55 newly diagnosed patients and 32 healthy controls using the sandwich enzyme-linked immunosorbent assay method. The medical records of the patients were also reviewed. Results: Serum CLP, S100A6, and HMGN1 levels were significantly decreased in MM patients compared to the control group (p=0.012, p=0.001, and p=0.030, respectively). Receiver operating characteristic analysis was used to determine diagnostic cut-off values for serum CLP, S100A6, and HMGN1 of <98 ng/mL (area under the curve [AUC]: 0.663, 95% confidence interval [CI]: 0.554-0.761, p=0.009), <1174.5 pg/mL (AUC: 0.706, 95% CI: 0.598-0.799, p=0.001), and <440.18 pg/mL (AUC: 0.640, 95% CI: 0.530-0.740, p=0.03), respectively. CLP levels were found to be statistically significantly higher in patients with light chain MM (91.58±22.57 ng/mL) compared to heavy chain MM (79.42±15.83 ng/mL) (p=0.03). A negative correlation was observed between CLP and M protein, immunoglobulin G, globulin, and beta-2 microglobulin (correlation coefficients: -0.361, -0.370, -0.279, -0.300, respectively; p=0.024, p=0.06, p=0.04, p=0.0033). Conclusion: In this study, we found that serum CLP, S100A6, and HMGN1 levels were statistically lower in patients with newly diagnosed MM compared to the control group. These results suggest that CLP may bind to the paraprotein produced by heavy chain MM in the blood, causing its blood levels to be low. Additionally, low levels of HMGN1, which is involved in DNA repair, suggest that HMGN1 may contribute to the complex genetic abnormalities found in cases of MM. [ABSTRACT FROM AUTHOR]

This document is a special issue of the International Journal of Molecular Sciences that focuses on the molecular mechanisms involved in epithelial-mesenchymal transition (EMT) and fibrosis. EMT is a process where epithelial cells acquire a mesenchymal morphology and is associated with various pathological conditions such as fibrosis and cancer. The issue includes fifteen original articles that cover a range of topics related to EMT and fibrosis, providing valuable insights into the molecular mechanisms underlying these conditions and offering potential therapeutic targets for further research. The articles explore the role of EMT in various human pathologies and its potential as a target for therapeutic interventions, covering topics such as fibrosis, preeclampsia, tissue engineering, and autoimmune thyroid diseases. The authors express their gratitude to the reviewers and contributors for their valuable contributions to this Special Issue. [Extracted from the article]

Background: Colorectal Cancer (CRC) represents a significant global health challenge, and its progression, resistance to therapy, and metastasis are strongly influenced by the tumor microenvironment, including factors like hypoxia. This study explores the impact of High Mobility Group Box 1 (HMGB1) overexpression on CRC cell migration, while identifying potential genes associated with this process. Methods: To explore this, we developed oncolytic virotherapy, resulting in HSV-HMGB1, an oncolytic Herpes simplex virus that expresses HMGB1. HMGB1 is known its role in cancer progression, particularly in the context of cancer cell migration. Results: Contrary to expectations, our scratch assays indicated that HSV-HMGB1 did not significantly induce migration in CRC cells, suggesting that HMGB1 might not directly contribute to this process. Employing microarray analysis, we investigated gene expression changes linked to CRC cell migration, leading to construction of a Protein-Protein Interaction (PPI) network. This network revealed the presence of hub proteins, including as NDRG1, LGALS1, and ANGPTL4, which are recognized for their roles in cancer cell migration. The differential expression of these genes under hypoxic conditions was further validated using quantitative RT-PCR, aligning with the findings from our microarray data. Conclusion: Our findings emphasize the complex regulation of CRC cell migration, and provides valuable insights into potential molecular mechanisms and pathways. These findings have implications for further research into cancer progression and the development of therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background and Purpose: Ischaemia–reperfusion (I/R) injury is a major contributor to skin flap necrosis, which presents a challenge in achieving satisfactory therapeutic outcomes. Previous studies showed that cathelicidin‐BF (BF‐30) protects tissues from I/R injury. In this investigation, BF‐30 was synthesized and its role and mechanism in promoting survival of I/R‐injured skin flaps explored. Experimental Approach: Survival rate analysis and laser Doppler blood flow analysis were used to evaluate I/R‐injured flap viability. Western blotting, immunofluorescence, TdT‐mediated dUTP nick end labelling (TUNEL) and dihydroethidium were utilized to examine the levels of apoptosis, pyroptosis, oxidative stress, transcription factor EB (TFEB)‐mediated autophagy and molecules related to the adenosine 5′‐monophosphate‐activated protein kinase (AMPK)–transient receptor potential mucolipin 1 (TRPML1)–calcineurin signalling pathway. Key Results: The outcomes revealed that BF‐30 enhanced I/R‐injured island skin flap viability. Autophagy, oxidative stress, pyroptosis and apoptosis were related to the BF‐30 capability to enhance I/R‐injured flap survival. Improved autophagy flux and tolerance to oxidative stress promoted the inhibition of apoptosis and pyroptosis in vascular endothelial cells. Activation of TFEB increased autophagy and inhibited endothelial cell oxidative stress in I/R‐injured flaps. A reduction in TFEB level led to a loss of the protective effect of BF‐30, by reducing autophagy flux and increasing the accumulation of reactive oxygen species (ROS) in endothelial cells. Additionally, BF‐30 modulated TFEB activity via the AMPK–TRPML1–calcineurin signalling pathway. Conclusion and Implications: BF‐30 promotes I/R‐injured skin flap survival by TFEB‐mediated up‐regulation of autophagy and inhibition of oxidative stress, which may have possible clinical applications. [ABSTRACT FROM AUTHOR]

In seeking alternative cancer treatments, antimicrobial peptides (AMPs), sourced from various life forms, emerge as promising contenders. These endogenous peptides, also known as host defense peptides (HDPs), play crucial roles in immune defenses against infections and exhibit potential in combating cancers. With their diverse defensive functions, plant-derived AMPs, such as thionins and defensins, offer a rich repertoire of antimicrobial properties. Insects, amphibians, and animals contribute unique AMPs like cecropins, temporins, and cathelicidins, showcasing broad-spectrum activities against bacteria, fungi, and viruses. Understanding these natural peptides holds significant potential for developing effective and targeted therapies against cancer and infectious diseases. Antimicrobial peptides (AMPs) exhibit diverse structural characteristics, including α-helical, β-sheet, extended, and loop peptides. Environmental conditions influence their structure, connecting to changes in cell membrane hydrophobicity. AMPs' actions involve direct killing and immune regulation, with additional activities like membrane depolarization. In this review, we focus on antimicrobial peptides that act as anticancer agents and AMPs that exhibit mechanisms akin to antimicrobial activity. Buforin AMPs, particularly Buforin I and II, derived from histone H2A, demonstrate antibacterial and anticancer potential. Buforin IIb and its analogs show promise, with selectivity for cancer cells. Despite the challenges, AMPs offer a unique approach to combat microbial resistance and potential cancer treatment. In various cancer types, including HeLa, breast, lung, ovarian, prostate, and liver cancers, buforins demonstrate inhibitory effects and apoptosis induction. To address limitations like stability and bioavailability, researchers explore buforin-containing bioconjugates, covalently linked with nanoparticles or liposomes. Bioconjugation enhances specificity-controlled release and combats drug resistance, presenting a promising avenue for targeted cancer treatment. Clinical translation awaits further evaluation through in vivo studies and future clinical trials. [ABSTRACT FROM AUTHOR]