Hypotensive drugs mitigate the high-sodium diet-induced pro-inflammatory activation of mouse macrophages in vivo.

Nowadays, there is an increasing emphasis on the need to alleviate the chronic inflammatory response to effectively treat hypertension. However, there are still gaps in our understanding on how to achieve this. Therefore, research on interaction of antihypertensive drugs with the immune system is extremely interesting, since their therapeutic effect could partly result from amelioration of hypertension-related inflammation, in which macrophages seem to play a pivotal role. Thus, current comprehensive studies have investigated the impact of repeatedly administered hypotensive drugs (captopril, olmesartan, propranolol, carvedilol, amlodipine, verapamil) on macrophage functions in the innate and adaptive immunity, as well as if drug-induced effects are affected by a high-sodium diet (HSD), one of the key environmental risk factors of hypertension. Although the assayed medications increased the generation of reactive oxygen and nitrogen intermediates by macrophages from standard fed donors, they reversed HSD-induced enhancing effects on macrophage oxidative burst and secretion of pro-inflammatory cytokines. On the other hand, some drugs increased macrophage phagocytic activity and the expression of surface markers involved in antigen presentation, which translated into enhanced macrophage ability to activate B cells for antibody production. Moreover, the assayed medications augmented macrophage function and the effector phase of contact hypersensitivity reaction, but suppressed the sensitization phase of cell-mediated hypersensitivity under HSD conditions. Our current findings contribute to the recognition of mechanisms, by which excessive sodium intake affects macrophage immune activity in hypertensive individuals, and provide evidence that the assayed medications mitigate most of the HSD-induced adverse effects, suggesting their additional protective therapeutic activity.

Immunomodulation by tramadol combined with acetaminophen or dexketoprofen: In vivo animal study.

Among other functions, macrophages remove foreign particles, including medications, from the circulation, making them an important target for immunomodulatory molecules. Currently, growing evidence suggests that analgesics affect the activity of immune cells not directly related to pain, and thus may induce unwanted immunosuppression in patients at risk. However, the immunomodulatory effects resulting from macrophage targeting by these drugs are understudied. Therefore, the current study investigated the immune effects induced in healthy mice by repeated administration of tramadol alone or in combination with acetaminophen or dexketoprofen. We observed that drug administration decreased the percentage of infiltrating macrophages in favor of resident macrophages in peritoneal exudates. While all drugs reduced the number of infiltrating macrophages that phagocytosed sheep red blood cells (SRBC), their administration increased the effectiveness of phagocytosis, and treatment with acetaminophen with or without tramadol elevated the expression of MHC class II by Mac3+ macrophages. Interestingly, SRBC-pulsed macrophages from mice treated with tramadol combined with acetaminophen potently activated SRBC-specific B cells in humoral response, and administration of these drugs to recipients of contact hypersensitivity effector cells augmented the resulting cellular immune response. In addition, tramadol administered alone or with dexketoprofen enhanced the spontaneous release of pro-inflammatory cytokines by macrophages. Our current research findings demonstrate that tramadol therapy in combination with acetaminophen or dexketoprofen has a relatively low risk of causing immunosuppressive side effect because the drugs slightly reduce the inflammatory reaction of macrophages but do not impair their ability to activate the adaptive immune responses.

Biodelivery of therapeutic extracellular vesicles: should mononuclear phagocytes always be feared?

At present, extracellular vesicles (EVs) are considered key candidates for cell-free therapies, including treatment of allergic and autoimmune diseases. However, their therapeutic effectiveness, dependent on proper targeting to the desired cells, is significantly limited due to the reduced bioavailability resulting from their rapid clearance by the cells of the mononuclear phagocyte system (MPS). Thus, developing strategies to avoid EV elimination is essential when applying them in clinical practice. On the other hand, malfunctioning MPS contributes to various immune-related pathologies. Therapeutic reversal of these effects with EVs would be beneficial and could be achieved, for example, by modulating the macrophage phenotype or regulating antigen presentation by dendritic cells. Additionally, intended targeting of EVs to MPS macrophages for replication and repackaging of their molecules into new vesicle subtype can allow for their specific targeting to appropriate populations of acceptor cells. Herein, we briefly discuss the under-explored aspects of the MPS-EV interactions that undoubtedly require further research in order to accelerate the therapeutic use of EVs.

Biological Properties of 12 Newly Isolated Acinetobacter baumannii-Specific Bacteriophages.

Infections with the opportunistic Gram-negative bacterium Acinetobacter baumannii pose a serious threat today, which is aggravated by the growing problem of multi-drug resistance among bacteria, caused by the overuse of antibiotics. Treatment of infections caused by antibiotic-resistant A. baumannii strains with the use of phage therapy is not only a promising alternative, but sometimes the only option. Therefore, phages specific for clinical multi-drug resistant A. baumannii were searched for in environmental, municipal, and hospital wastewater samples collected from different locations in Poland. The conducted research allowed us to determine the biological properties and morphology of the tested phages. As a result of our research, 12 phages specific for A. baumannii, 11 of which turned out to be temperate and only one lytic, were isolated. Their lytic spectra ranged from 11 to 75%. The plaques formed by most phages were small and transparent, while one of them formed relatively large plaques with a clearly marked 'halo' effect. Based on Transmission Electron Microscopy (TEM), most of our phages have been classified as siphoviruses (only one phage was classified as a podovirus). All phages have icosahedral capsid symmetry, and 11 of them have a long tail. Optimal multiplicity of infections (MOIs) and the adsorption rate were also determined. MOI values varied depending on the phage-from 0.001 to 10. Based on similarities to known bacteriophages, our A. baumannii-specific phages have been proposed to belong to the Beijerinckvirinae and Junivirinae subfamilies. This study provides an additional tool in the fight against this important pathogen and may boost the interest in phage therapy as an alternative and supplement to the current antibiotics.

Extracellular Vesicles-Oral Therapeutics of the Future.

Considered an artifact just after discovery, the possibility of oral delivery of extracellular vesicles (EVs) and their functional cargos has recently gained much research attention. EVs from various sources, including edible plants, milk, bacteria and mammalian cells, have emerged as a platform for miRNA and drug delivery that seem to induce the expected immune effects locally and in distant tissues after oral administration. Such a possibility greatly expands the clinical applicability of EVs. The present review summarizes research findings that either support or deny the biological/therapeutical activity of orally administered EVs and their role in cross-species and cross-kingdom signaling.

Two Newly Isolated Enterobacter-Specific Bacteriophages: Biological Properties and Stability Studies.

In an era of antibiotic therapy crisis caused by spreading antimicrobial resistance, and when recurrent urinary tract infections constitute a serious social and medical problem, the isolation and complex characterization of phages with a potential therapeutic application represents a promising solution. It is an inevitable, and even a necessary direction in the development of current phage research. In this paper, we present two newly isolated myoviruses that show lytic activity against multidrug-resistant clinical isolates of Enterobacter spp. (E. cloacae, E. hormaechei, and E. kobei), the genomes of which belong to a poorly represented phage group. Both phages were classified as part of the Tevenvirinae subfamily (Entb_43 was recognized as Karamvirus and Entb_45 as Kanagawavirus). Phage lytic spectra ranging from 40 to 60% were obtained. The most effective phage-to-bacteria ratios (MOI = 0.01 and MOI = 0.001) for both the phage amplification and their lytic activity against planktonic bacteria were also estimated. Complete adsorption to host cells were obtained after about 20 min for Entb_43 and 10 min for Entb_45. The phage lysates retained their initial titers even during six months of storage at both -70 °C and 4 °C, whereas storage at 37 °C caused a complete loss in their activity. We showed that phages retained their activity after incubation with solutions of silver and copper nanoparticles, which may indicate possible synergistic antibacterial activity. Moreover, a significant reduction in phage titers was observed after incubation with a disinfectant containing octenidinum dihydrochloridum and phenoxyethanol, as well as with 70% ethanol. The observed maintenance of phage activity during incubation in a urine sample, along with other described properties, may suggest a therapeutic potential of phages at the infection site after intravesical administration.

What Are the Potential Benefits of Using Bacteriophages in Periodontal Therapy?

Periodontitis, which may result in tooth loss, constitutes both a serious medical and social problem. This pathology, if not treated, can contribute to the development of, among others, pancreatic cancer, cardiovascular diseases or Alzheimer's disease. The available treatment methods are expensive but not always fully effective. For this reason, the search for and isolation of bacteriophages specific to bacterial strains causing periodontitis seems to be a great opportunity to target persistent colonization by bacterial pathogens and lower the use of antibiotics consequently limiting further development of antibiotic resistance. Furthermore, antimicrobial resistance (AMR) constitutes a growing challenge in periodontal therapy as resistant pathogens may be isolated from more than 70% of patients with periodontitis. The aim of this review is to present the perspective of phage application in the prevention and/or treatment of periodontitis alongside its complicated multifactorial aetiology and emphasize the challenges connecting composition and application of effective phage preparation.

Human ß-Defensin 2 and Its Postulated Role in Modulation of the Immune Response.

Studies described so far suggest that human ß-defensin 2 is an important protein of innate immune response which provides protection for the human organism against invading pathogens of bacterial, viral, fungal, as well as parasitical origin. Its pivotal role in enhancing immunity was proved in infants. It may also be considered a marker of inflammation. Its therapeutic administration has been suggested for maintenance of the balance of systemic homeostasis based on the appropriate composition of the microbiota. It has been suggested that it may be an important therapeutic tool for modulating the response of the immune system in many inflammatory diseases, offering new treatment modalities. For this reason, its properties and role in the human body discussed in this review should be studied in more detail.

Isolation and Characterization of Phages Active against Paenibacillus larvae Causing American Foulbrood in Honeybees in Poland.

The aim of this study was the isolation and characterization, including the phage effect on honeybees in laboratory conditions, of phages active against Paenibacillus larvae, the causative agent of American Foulbrood-a highly infective and easily spreading disease occurring in honeybee larva, and subsequently the development of a preparation to prevent and treat this dangerous disease. From the tested material (over 2500 samples) 35 Paenibacillus spp. strains were obtained and used to search for phages. Five phages specific to Paenibacillus were isolated and characterized (ultrastructure, morphology, biological properties, storage stability, and genome sequence). The characteristics were performed to obtain knowledge of their lytic potential and compose the final phage cocktail with high antibacterial potential and intended use of future field application. Preliminary safety studies have also been carried out on healthy bees, which suggest that the phage preparation administered is harmless.

Temperate Bacteriophages-The Powerful Indirect Modulators of Eukaryotic Cells and Immune Functions.

Bacteriophages are natural biological entities that limit the growth and amplification of bacteria. They are important stimulators of evolutionary variability in bacteria, and currently are considered a weapon against antibiotic resistance of bacteria. Nevertheless, apart from their antibacterial activity, phages may act as modulators of mammalian immune responses. In this paper, we focus on temperate phages able to execute the lysogenic development, which may shape animal or human immune response by influencing various processes, including phagocytosis of bacterial invaders and immune modulation of mammalian host cells.

The Role of Antibiotic Resistant A. baumannii in the Pathogenesis of Urinary Tract Infection and the Potential of Its Treatment with the Use of Bacteriophage Therapy.

Acinetobacter baumannii are bacteria that belong to the critical priority group due to their carbapenems and third generation cephalosporins resistance, which are last-chance antibiotics. The growing multi-drug resistance and the ability of these bacteria to form biofilms makes it difficult to treat infections caused by this species, which often affects people with immunodeficiency or intensive care unit patients. In addition, most of the infections are associated with catheterization of patients. These bacteria are causative agents, inter alia, of urinary tract infections (UTI) which can cause serious medical and social problems, because of treatment difficulties as well as the possibility of recurrence and thus severely decrease patients' quality of life. Therefore, a promising alternative to standard antibiotic therapy can be bacteriophage therapy, which will generate lower costs and will be safer for the treated patients and has real potential to be much more effective. The aim of the review is to outline the important role of drug-resistant A. baumannii in the pathogenesis of UTI and highlight the potential for fighting these infections with bacteriophage therapy. Further studies on the use of bacteriophages in the treatment of UTIs in animal models may lead to the use of bacteriophage therapy in human urinary tract infections caused by A. baumannii in the future.

Animal Models in the Evaluation of the Effectiveness of Phage Therapy for Infections Caused by Gram-Negative Bacteria from the ESKAPE Group and the Reliability of Its Use in Humans.

The authors emphasize how extremely important it is to highlight the role played by animal models in an attempt to determine possible phage interactions with the organism into which it was introduced as well as to determine the safety and effectiveness of phage therapy in vivo taking into account the individual conditions of a given organism and its physiology. Animal models in which phages are used make it possible, among other things, to evaluate the effective therapeutic dose and to choose the possible route of phage administration depending on the type of infection developed. These results cannot be applied in detail to the human body, but the knowledge gained from animal experiments is invaluable and very helpful. We would like to highlight how useful animal models may be for the possible effectiveness evaluation of phage therapy in the case of infections caused by gram-negative bacteria from the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species) group of pathogens. In this review, we focus specifically on the data from the last few years.