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Paulina Paprocka,1 Bonita Durnaś,1,2 Angelika Mańkowska,1 Karol Skłodowski,3 Grzegorz Król,1 Magdalena Zakrzewska,3 Michał Czarnowski,3 Patrycja Kot,1 Kamila Fortunka,1 Stanisław Góźdź,2 Paul B Savage,4 Robert Bucki1,3 1Department of Microbiology and Immunology, Institute of Medical Science, Collegium Medicum, Jan Kochanowski University in Kielce, Kielce, Poland; 2Holy Cross Oncology Center of Kielce, Kielce, Poland; 3Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Białystok, Białystok, Poland; 4Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, USACorrespondence: Robert Bucki Tel +48-85-7485493Fax +48-85 748 54 16Email buckirobert@gmail.comBackground: The increasing number of infections caused by antibiotic resistant strains of Pseudomonas aeruginosa posed a very serious challenge for clinical practice. This standing is driving scientists to develop new antibiotics against these microorganisms.Methods: In this study, we measured the MIC/MBC values and estimated the ability of tested molecules to prevent bacterial biofilm formation to explore the effectiveness of β-lactam antibiotics ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, and ceragenins CSA-13, CSA-44, and CSA-131 against 150 clinical isolates of Pseudomonas aeruginosa that were divided into five groups, based on their antibiotic resistance profiles to beta-lactams. Selected strains of microorganisms from each group were also subjected to prolonged incubations (20 passages) with ceragenins to probe the development of resistance towards those molecules. Cytotoxicity of tested ceragenins was evaluated using human red blood cell (RBCs) hemolysis and microscopy observations of human lung epithelial A549 cells after ceragenin treatment. Poloxamer 407 (pluronic F-127) at concentrations ranging from 0.5% to 5% was tested as a potential drug delivery substrate to reduce ceragenin toxicity.Results: Collected data proved that ceragenins at low concentrations are highly active against clinical strains of Pseudomonas aeruginosa regardless of their resistance mechanisms to conventional antibiotics. Ceragenins also show low potential for resistance development, high antibiofilm activity, and controlled toxicity when used together with poloxamer 407.Conclusion: This data strongly supports the need for further study directed to develop this group of molecules as new antibiotics to fighting infections caused by antibiotic resistant strains of Pseudomonas aeruginosa.Keywords: ceragenin, antibacterial agents, Pseudomonas aeruginosa, antibiotic resistant bacteria, new antibiotics

Katarzyna Niemirowicz-Laskowska,1 Katarzyna Głuszek,1 Ewelina Piktel,1 Karlis Pajuste,2 Bonita Durnaś,3 Grzegorz Król,3 Agnieszka Z Wilczewska,4 Paul A Janmey,5 Aiva Plotniece,2 Robert Bucki1 1Department of Microbiological and Nanobiomedical Engineering, Medical University of Bialystok, Bialystok, Poland; 2Laboratory of Membrane Active Compounds and β-Diketones, Latvian Institute of Organic Synthesis, Riga, Latvia; 3Department of Microbiology and Immunology, The Faculty of Health Sciences of the Jan Kochanowski University in Kielce, Kielce, 4Institute of Chemistry, University of Bialystok, Białystok, Poland; 5Department of Physiology, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA Background: 1,4-Dihydropyridine (1,4-DHP) and its derivatives are well-known calcium channel blockers with antiarrhythmic and antihypertensive activities. These compounds exhibit pleiotropic effects including antimicrobial activities that rely on their positive charge and amphipathic nature. Use of magnetic nanoparticles (MNPs) as carriers of 1,4-DHP modulates their properties and enables improved formulations with higher efficacy and less toxicity. Methods: In this study, the antimicrobial and immunomodulatory activities of novel 1,4-DHP derivatives in free form and immobilized on MNPs were determined by evaluating pathogen outgrowth and proinflammatory cytokine release in experimental settings that involve incubation of various 1,4-DHPs with clinical isolates of bacteria or fungi as well as mammalian cell culture models. Results: Conventional immobilization of 1,4-DHP on aminosilane-coated MNPs markedly enhances their antimicrobial activity compared to nonimmobilized molecules, in part because of the higher affinity of these nanosystems for bacterial cell wall components in the presence of human body fluids. Conclusion: Optimized nanosystems are characterized by improved biocompatibility and higher anti-inflammatory properties that provide new opportunities for the therapy of infectious diseases. Keywords: magnetic nanoparticles, 1,4-dihydropyridine, antibacterial, antifungal, immunomodulatory properties

Acne vulgaris (AV) is a chronic inflammatory condition of the pilosebaceous units characterized by multiple immunologic, metabolic, hormonal, genetic, psycho-emotional dysfunctions, and skin microbiota dysbiosis. The latter is manifested by a decreased population (phylotypes, i.e., genetically distinct bacterial subgroups that play different roles in skin health and disease) diversity of the predominant skin bacterial commensal - Cutinbacterium acnes . Like in other dysbiotic disorders, an elevated expression of endogenous antimicrobial peptides (AMPs) is a hallmark of AV. AMPs, such as human β-defensins, cathelicidin LL-37, dermcidin, or RNase-7, due to their antibacterial and immunomodulatory properties, function as the first line of defense and coordinate the host-microbiota interactions. Therefore, AMPs are potential candidates for pharmaceutical prophylaxis or treating this condition. This study outlines the current knowledge regarding the importance of AMPs in AV pathomechanism in light of recent transcriptomic studies. In particular, their role in improving the tight junctions (TJs) skin barrier by activating the fundamental cellular proteins, such as PI3K, GSK-3, aPKC, and Rac1, is discussed. We hypothesized that the increased expression of AMPs and their patterns in AV act as a compensatory mechanism to protect the skin with an impaired permeability barrier. Therefore, AMPs could be key determinants in regulating AV development and progression, linking acne-associated immune responses and metabolic factors, like insulin/IGF-1 and PI3K/Akt/mTOR/FoxO1 signaling pathways or glucotoxicity. Research and development of anti-acne AMPs are also addressed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Lesiak, Paprocka, Wnorowska, Mańkowska, Król, Głuszek, Piktel, Spałek, Okła, Fiedoruk, Durnaś and Bucki.)

Background/Objectives : Histopathological examination enables visualization of morphological changes in cells and tissues. In recent years, there has been increasing interest in assessing the mechanical properties of tissues that cannot be determined by standard histopathological examinations. Mechanobiology is crucial in human physiology and holds promise for uncovering new diagnostic markers for disease processes such as carcinogenesis and inflammation. In this study, we concentrated on measuring the mechanical properties of appendix biopsy specimens to identify potential mechanomarkers of inflammation. Appendix tissues provided the opportunity to measure mechanical properties both with an atomic force microscope and a shear rheometer. Methods : The atomic force microscope AFM-NanoWizard 4 BioScience JPK/Bruker was used for the evaluation of the elastic modulus (i.e., Young's modulus) of appendix tissues. Young's modulus was derived from the Hertz-Sneddon model applied to force-indentation curves. The rheological properties of macroscopic samples were measured on a parallel-plate, strain-controlled shear rheometer Anton Paar MCR302. Results : The data collected suggest that elasticity, expressed as Young's modulus and the storage modulus, could be considered a marker indicating appendix tissue inflammation. Young's modulus of inflamed appendix tissues was found to be significantly lower than that of healthy ones, with an average reduction of 67%. Furthermore, it was observed that inflamed appendix tissues, in comparison to healthy ones, respond differently under varying axial and shear stresses, enabling their identification. Conclusions : Our findings suggest that the specific mechanical properties of inflamed vermiform appendices could serve as novel mechanomarkers for the early detection and monitoring of appendicitis.

Ensuring proper dental hygiene is of paramount importance for individuals' general well-being, particularly for patients receiving medical care. There is a prevailing utilization of conventional oral hygiene items, including toothbrushes and mouthwashes, which have gained widespread acceptance; nevertheless, their limitations encourage investigating novel options in this domain. Our study indicates that ceragenins (CSAs) being lipid analogs of host defense peptides, well-recognized for their wide-ranging antimicrobial properties, may be a potentially efficacious means to augment oral hygiene in hospitalized individuals. We demonstrate that ceragenins CSA-13, CSA-44, and CSA-131 as well as undescribed to date CSA-255 display potent antimicrobial activities against isolates of fungi, aerobic, and anaerobic bacteria from Candida , Streptococcus , Enterococcus , and Bacteroides species, which are well-recognized representatives of microbes found in the oral cavity. These effects were further confirmed against mono- and dual-species fungal and bacterial biofilms. While the ceragenins showed similar or slightly diminished efficacy compared to commercially available mouthwashes, they demonstrated a highly favorable toxicity profile toward host cells, that may translate into better maintenance of host mucosal membrane stability. This suggests that incorporating ceragenins into oral hygiene products could be a valuable strategy for reducing the risk of both oral cavity-localized and secondary systemic infections and for improving the overall health outcomes of individuals receiving medical treatment.

The growing number of infections caused by multidrug-resistant bacterial strains, limited treatment options, multi-species infections, high toxicity of the antibiotics used, and an increase in treatment costs are major challenges for modern medicine. To remedy this, scientists are looking for new antibiotics and treatment methods that will effectively eradicate bacteria while continually developing different resistance mechanisms. Ceragenins are a new group of antimicrobial agents synthesized based on molecular patterns that define the mechanism of antibacterial action of natural antibacterial peptides and steroid-polyamine conjugates such as squalamine. Since ceragenins have a broad spectrum of antimicrobial activity, with little recorded ability of bacteria to develop a resistance mechanism that can bridge their mechanism of action, there are high hopes that this group of molecules can give rise to a new family of drugs effective against bacteria resistant to currently used antibiotics. Experimental data suggests that core-shell nanosystems, in which ceragenins are presented to bacterial cells on metallic nanoparticles, may increase their antimicrobial potential and reduce their toxicity. However, studies should be conducted, among others, to assess potential long-term cytotoxicity and in vivo studies to confirm their activity and stability in animal models. Here, we summarized the current knowledge on ceragenins and ceragenin-containing nanoantibiotics as potential new tools against emerging Gram-negative rods associated with nosocomial infections.

The usage of nanotechnology in the fight against parasitic diseases is in the early stages of development, but it brings hopes that this new field will provide a solution to target the early stages of parasitosis, compensate for the lack of vaccines for most parasitic diseases, and also provide new treatment options for diseases in which parasites show increased resistance to current drugs. The huge physicochemical diversity of nanomaterials developed so far, mainly for antibacterial and anti-cancer therapies, requires additional studies to determine their antiparasitic potential. When designing metallic nanoparticles (MeNPs) and specific nanosystems, such as complexes of MeNPs, with the shell of attached drugs, several physicochemical properties need to be considered. The most important are: size, shape, surface charge, type of surfactants that control their dispersion, and shell molecules that should assure specific molecular interaction with targeted molecules of parasites' cells. Therefore, it can be expected that the development of antiparasitic drugs using strategies provided by nanotechnology and the use of nanomaterials for diagnostic purposes will soon provide new and effective methods of antiparasitic therapy and effective diagnostic tools that will improve the prevention and reduce the morbidity and mortality caused by these diseases.

Ceragenins (CSAs) are synthetic, lipid-based molecules that display activities of natural antimicrobial peptides. Previous studies demonstrated their high in vitro activity against pathogens causing urinary tract infections (UTIs), but their efficiency in vivo was not explored to date. In this study, we aimed to investigate the bactericidal efficiency of ceragenins against E. coli (Xen14 and clinical UPEC strains) isolates both in vitro and in vivo, as well to explore CSA-13 biodistribution and ability to modulate nanomechanical alterations of infected tissues using animal model of UTI. CSA-44, CSA-131 and particularly CSA-13 displayed potent bactericidal effect against tested E. coli strains, and this effect was mediated by induction of oxidative stress. Biodistribution studies indicated that CSA-13 accumulates in kidneys and liver and is eliminated with urine and bile acid. We also observed that ceragenin CSA-13 reverses infection-induced alterations in mechanical properties of mouse bladders tissue, which confirms the preventive role of CSA-13 against bacteria-induced tissue damage and potentially promote the restoration of microenvironment with biophysical features unfavorable for bacterial growth and spreading. These data justify the further work on employment of CSA-13 in the treatment of urinary tract infections., (© 2022. The Author(s).)

It has been proven that tumour growth and progression are regulated by a variety of mediators released during the inflammatory process preceding the tumour appearance, but the role of inflammation in the development of bladder cancer is ambiguous. This study was designed around the hypothesis that sphingosine-1-phosphate (S1P), as a regulator of several cellular processes important in both inflammation and cancer development, may exert some of the pro-tumorigenic effects indirectly due to its ability to regulate the expression of human cathelicidin (hCAP-18). LL-37 peptide released from hCAP-18 is involved in the development of various types of cancer in humans, especially those associated with infections. Using immunohistological staining, we showed high expression of hCAP-18/LL-37 and sphingosine kinase 1 (the enzyme that forms S1P from sphingosine) in human bladder cancer cells. In a cell culture model, S1P was able to stimulate the expression and release of hCAP-18/LL-37 from human bladder cells, and the addition of LL-37 peptide dose-dependently increased their proliferation. Additionally, the effect of S1P on LL-37 release was inhibited in the presence of FTY720P, a synthetic immunosuppressant that blocks S1P receptors. Together, this study presents the possibility of paracrine relation in which LL-37 production following cell stimulation by S1P promotes the development and growth of bladder cancer.

P seudomonas aeruginosa ( P. aeruginosa to antibiotics make the treatment of infections caused by this microorganism a growing challenge. Although novel antibiotics expand the arsenal of antipseudomonal drugs, they do not show activity against all strains, e.g., MBL (metalo-β-lactamase) producers. Moreover, resistance to novel antibiotics has already emerged. Consequently, preventive methods such as limiting the transmission of resistant strains, active surveillance screening for MDR (multidrug-resistant) strains colonization, microbiological diagnostics, antimicrobial stewardship and antibiotic prophylaxis are of particular importance in cancer patients. Unfortunately, surveillance screening in the case of P. aeruginosa to antibiotics make the treatment of infections caused by this microorganism a growing challenge. Although novel antibiotics expand the arsenal of antipseudomonal drugs, they do not show activity against all strains, e.g., MBL (metalo-β-lactamase) producers. Moreover, resistance to novel antibiotics has already emerged. Consequently, preventive methods such as limiting the transmission of resistant strains, active surveillance screening for MDR (multidrug-resistant) strains colonization, microbiological diagnostics, antimicrobial stewardship and antibiotic prophylaxis are of particular importance in cancer patients. Unfortunately, surveillance screening in the case of P. aeruginosa is not highly effective, and a fluoroquinolone prophylaxis in the era of increasing resistance to antibiotics is controversial.

Background: Stenotrophomonas maltophilia ( S. maltophilia ) is an emerging opportunistic Gram-negative rod causing nosocomial infections predominantly in immunocompromised patients. Due to its broad intrinsic resistance to antibiotics, including carbapenems and the ability to form a biofilm, it is difficult to eradicate., Methods: In this study, the benefit of combined administration (potential synergism) and anti-biofilm activity of ceragenins: CSA-13, CSA-44, and CSA-131 (synthetic mimics of natural antimicrobial peptides) with ceftazidime, levofloxacin, co-trimoxazole and colistin against clinical strains of S. maltophilia were determined using MIC/MBC (minimum inhibitory concentration/minimum bactericidal concentration), killing assays and CV staining., Results: Obtained data indicate that the ceragenins exhibit strong activity against the tested strains of S. maltophilia grown in planktonic culture and as stationary biofilms. Moreover, with some strains, the synergy of ceragenins with conventional antibiotics was observed Conclusion: Our data suggest that ceragenins are promising agents for future development of new methods for treatment of infections caused by S. maltophilia , along with its potential use in combination with conventional antibiotics.

For decades, biomaterials have been commonly used in medicine for the replacement of human body tissue, precise drug-delivery systems, or as parts of medical devices that are essential for some treatment methods. Due to rapid progress in the field of new materials, updates on the state of knowledge about biomaterials are frequently needed. This article describes the clinical application of different types of biomaterials in the field of otorhinolaryngology, i.e., head and neck surgery, focusing on their antimicrobial properties. The variety of their applications includes cochlear implants, middle ear prostheses, voice prostheses, materials for osteosynthesis, and nasal packing after nasal/paranasal sinuses surgery. Ceramics, such as as hydroxyapatite, zirconia, or metals and metal alloys, still have applications in the head and neck region. Tissue engineering scaffolds and drug-eluting materials, such as polymers and polymer-based composites, are becoming more common. The restoration of life tissue and the ability to prevent microbial colonization should be taken into consideration when designing the materials to be used for implant production. The authors of this paper have reviewed publications available in PubMed from the last five years about the recent progress in this topic but also establish the state of knowledge of the most common application of biomaterials over the last few decades.

Background: Acute pancreatitis (AP) is a frequent hospitalization cause of patients suffering from gastrointestinal disorders. Gelsolin has an ability to bind bioactive lipids including different sphingolipids engaged in inflammatory response. Importantly, hypogelsolinemia was observed in patients with different states of acute and chronic inflammation., Aims: The aim of the present study was to assess the interplay of blood plasma gelsolin and blood plasma sphingosine-1-phosphate (S1P) concentration in patients diagnosed with acute pancreatitis., Materials and Methods: To assess the concentration of gelsolin and S1P, immunoblotting and HPLC technique were employed, respectively. Additionally, the concentrations of amylase, lipase, C-reactive protein (CRP), procalcitonin (PCT) and the number of white blood cells (WBC) and platelet (PLT) were recorded., Results: We found that both pGSN and S1P concentrations in the plasma of the AP patients were significantly lower (pGSN ~ 15-165 mg/L; S1P ~ 100-360 pmol/mL) when compared to the levels of pGSN and S1P in a control group (pGSN ~ 130-240 mg/L; S1P ~ 260-400 pmol/mL). Additionally, higher concentrations of CRP, WBC, amylase and lipase were associated with low level of gelsolin in the blood of AP patients. No correlations between the level of PCT and PLT with gelsolin concentration were noticed., Conclusion: Plasma gelsolin and S1P levels decrease during severe acute pancreatitis. Simultaneous assessment of pGSN and S1P can be useful in development of more accurate diagnostic strategies for patients with severe acute pancreatitis., (© 2021. The Author(s).)

Background: The combustion of tobacco is the main cause of tobacco-related morbidity and mortality. E-cigarettes are potentially disruptive innovations with considerable potential for population health. A key question is whether e-cigarettes are replacing tobacco cigarettes, which requires mapping their prevalence. Collecting information on nicotine use is difficult for many countries due to cost. The objective of this study was to derive a global estimate of e-cigarette use (vaping)., Methods: Since 2018 we have collected information on the prevalence of e-cigarette use. To estimate the prevalence of vaping in countries lacking information, we used the method of assumed similarity between countries in the same region and economic condition. Based on surveys, we calculated the average prevalence of vaping for each WHO region, World Bank income classification group, and the legal status of e-cigarettes in each country. For each of these groups the average prevalence of vaping was calculated. These values were used as substitutes for the prevalence figures in the countries with absent data. The number of vapers was calculated by taking as the denominator the adult population., Results: Survey data on e-cigarette users were available for 49 countries covering 2.8 b of the adult population in 2018 and unavailable for 2.9 b. Information on vaping was lacking for half of the world's population. We estimated a total of 58.1 m vapers worldwide in 2018. By reference to market growth the data were adjusted to arrive at estimates for 2020. Results were fitted to revenue data at the 2018. For the year 2020, the projection is for 68 m vapers globally., Conclusions: Many global epidemiological studies use the method of assumed similarity between countries with shared characteristics in order to estimate missing data. The methodological limitations are likely to overestimate the global number of vapers. Our estimate of 68 m vapers indicates considerable uptake given that: e-cigarettes have been available on most markets for only a decade; there is either no support, or there is opposition to vaping in many countries; and countries which regulate e-cigarettes have controls over advertising and promotion. However, given the global scale of tobacco smoking (at 1.1 billion people), progress in adoption of alternative products is slow. Those using e-cigarettes are still a small fraction of those who smoke., (© 2021. The Author(s).)

Oral leukoplakia is a clinical term relating to various morphological lesions, including squamous cell hyperplasia, dysplasia and carcinoma. Leukoplakia morphologically manifested as hyperplasia with epithelial dysplasia is clinically treated as precancerous condition. Nevertheless, there is a lack of good markers indicating the transformation of premalignancies towards cancer. A better understanding of the mechanical environment within the tissues where tumors grow might be beneficial for the development of prevention, diagnostic, and treatment methods in cancer management. Atomic force microscopy (AFM) and immunohistology techniques were used to assess changes in the stiffness and morphology of oral mucosa and leukoplakia samples at different stages of their progression towards cancer. The Young's moduli of the tested leukoplakia samples were significantly higher than those of the surrounding mucus. Robust inhomogeneity of stiffness within leukoplakia samples, reflecting an increase in regeneration and collagen accumulation (increasing density) in the extracellular matrix (ECM), was observed. Within the histologically confirmed cancer samples, Young's moduli were significantly lower than those within the precancerous ones. Inhomogeneous stiffness within leukoplakia might act as "a mechanoagonist" that promotes oncogenesis. In contrast, cancer growth might require the reorganization of tissue structure to create a microenvironment with lower and homogenous stiffness. The immunohistology data collected here indicates that changes in tissue stiffness are achieved by increasing cell/ECM density. The recognition of new markers of premalignancy will aid in the development of new therapies and will expand the diagnostic methods., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Inc.)

Medical device-associated infections are a serious medical threat, particularly for patients with impaired mobility and/or advanced age. Despite a variety of antimicrobial coatings for medical devices being explored to date, only a limited number have been introduced for clinical use. Research into new bactericidal agents with the ability to eradicate pathogens, limit biofilm formation, and exhibit satisfactory biocompatibility, is therefore necessary and urgent. In this study, a series of varied-morphology gold nanoparticles in shapes of rods, peanuts, stars and spherical-like, porous ones with potent antibacterial activity were synthesized and thoroughly tested against spectrum of Candida albicans, Pseudomonas aeruginosa, Staphylococcus aureus clinical strains, as well as spectrum of uropathogenic Escherichia coli isolates. The optimization of gold nanoparticles synthesis allowed to develop nanomaterials, which are proved to be significantly more potent against tested microbes compared with the gold nanoformulations reported to date. Notably, their antimicrobial spectrum includes strains with different drug resistance mechanisms. Facile and cost-efficient synthesis of gold nanoparticles, remarkable bactericidal efficiency at nanogram doses, and low toxicity, underline their potential for development as a new coatings, as indicated by the example of urological catheters. The presented research fills a gap in microbial studies of non-spherical gold nanoparticles for the development of antimicrobial coatings targeting multidrug-resistant pathogens responsible for device-associated nosocomial infections.