Rola i potencjał terapeutyczny sfingolipidowego szlaku sygnalizacyjnego w nowotworach hematologicznych

One of the key obstacles in the progress of cancer treatment is the lack of balance between theuncontrolled proliferation and cell apoptosis. It is now known that sphingolipids are essentialmolecules regulating the processes of growth, differentiation and death of living cells. Dependingon their chemical nature, sphingolipids may have a stimulatory (S1P, sphingosine-1-phosphate)or inhibitory (ceramide) effect on cellular proliferation. A number of different studies have shownthat the generation of ceramide in response to cytotoxic therapy is an important element leadingto cell death. Cancer cells use different methods limiting the production of ceramides that leads totheir removal. The effect of oncogenic S1P results from its stimulating effect on DNA synthesisand chemotactic mobility of the vascular endothelial cells and angiogenesis. The use of monoclonalanti-S1P antibodies is potentially a valuable therapeutic option for inhibiting angiogenesisdetermining the growth of tumors. It was additionally demonstrated that S1P beyond the directand indirect by stimulating the release of vascular endothelial growth factor and basic fibroblastgrowth factor angiogenic action has an effect on tumor growth and its metastatic potential. Amongthe sphingolipids, ceramide was identified first as inducing differentiation and the death of humanHL-60 promyelocytic leukemia cells. Progress in understanding the role of sphingolipids wasregarded until recently as the only structural component of cell membranes allowing the use in thetreatment of complex properties of this group of signaling molecules. Thus, it has become importantto clarify the role of sphingolipids in the regulation of the balance between proliferation signals//survival rate and death of cells in order to develop new therapies for neoplastic diseases of myeloidand lymphoid origin.Brak skutecznych metod pozwalających na osiągnięcie równowagi między niekontrolowaną proliferacją i apoptozą komórek w procesie nowotworowym stanowi jedną z kluczowych barier postępu w leczeniu. Obecnie wiadomo, że istotnymi cząsteczkami regulującymi procesy wzrostu, różnicowania, życia oraz śmierci komórek są sfingolipidy. Zależnie od natury chemicznej sfingolipidy mogą pobudzać (S1P, sfingozyno-1-fosforan) lub hamować (ceramid) proliferację. W wielu różnych badaniach wykazano, że generacja ceramidu w odpowiedzi na terapię cytotoksyczną jest ważnym elementem prowadzącym do śmierci komórki. Komórki nowotworowe stosują różne sposoby ograniczające wytwarzanie ceramidu i prowadzące do jego usuwania. Działanie onkogenne S1P wynika z jego działania stymulującego syntezę DNA i ruchliwość chemotaktyczną komórek śródbłonka naczyniowego, jak również stymulacji rozwoju naczyń krwionośnych. Dlatego zastosowanie przeciwciał monoklonalnych anty-S1P jest potencjalnie wartościową opcją terapeutyczną w hamowaniu rozwoju naczyń krwionośnych warunkujących wzrost guzów nowotworowych. Dodatkowo udowodniono, że S1P poza bezpośrednim oraz pośrednim — przez stymulację uwalniania czynnika wzrostu śródbłonka naczyniowego i podstawowy czynnik wzrostu fibroblastów — działaniem angiogennym, wpływa na wzrost i potencjał przerzutowy nowotworów. Spośród sfingolipidów ceramid wskazano jako pierwszy indukujący różnicowanie i śmierć w komórkach ludzkiej białaczki promielocytowej HL-60. Postęp w zrozumieniu roli sfingolipidów, uważanych do niedawna za jedynie składową strukturalną błon komórkowych, umożliwia wykorzystanie w terapii złożonych właściwości tej grupy cząsteczek sygnalizacyjnych. Istotne więc stało się wyjaśnienie roli sfingolipidów w regulacji równowagi między sygnałami proliferacji/przeżywalności komórek i ich śmierci w celu opracowania nowych terapii

Knowledge about sexual transmitted disease (STDs) and risks involved amongst young people population living in south-eastern region of Poland

Introduction: Sexually transmitted diseases (STD) are considered to be a serious health matter with the numbers of cases continuously increasing. Numerous studies have pointed out that Polish youth do not have a sufficient knowledge of the risks involved with contracting STD, mainly because there are no effective sexual education within schools, families or medical institutions. Aim: The aim of this research was to investigate the level of knowledge concerning STD amongst the population of young adults between 19 and 24 years old living in the South-eastern region of Poland. Methods and Materials: The analysis was comprised of 104 people between 19-24 years old from which 57.7% were women and 42.3% were men. The method used to conduct described research was a diagnostic survey, from which a questionnaire created by the author was used alongside a Polish adaptation of the Multidimensional Health Locus of Control (MHLC). The analysis was carried out using Statistical 13 PL program. Results:  More than half (54.8%) of those surveyed believed that STD contraction could only be possible via sexual intercourse. Amongst those surveyed the most known itemized STDs were HIV/AIDS (93.3%), genital herpes (86.5%), gonorrhoea (84.6%) and syphilis (80.8%). The knowledge of those surveyed was based on the information obtained through the internet (67.3%), leaflets and handouts (28.8%), television (22.1%) and lastly parents (1.9%). In the opinion of participating surveyed sexual education should come from a gynaecologist or sexual health professional (61.5%) or an experienced pedagogue (18.3%). There was no difference in STD knowledge between women and men (p>0.05). There was a significant difference in knowledge which was shown in the results of those surveyed between people with a basic and a higher education (p<0.05) with a statistically significant link between the ages of those surveyed and their knowledge (p<0.01). Conclusion: • The knowledge of those surveyed is unsystematic and incomplete. • Young people expect information from gynaecologist, sexual health professionals and experienced pedagogue. • The subject of STD should be addressed more not only in schools but also within their own home whilst highlighting the importance of the role of the parents in this aspect. • It is recommended to educate young people on where to obtain sufficient and adequate information from reliable sources

Plasma Gelsolin: Indicator of Inflammation and Its Potential as a Diagnostic Tool and Therapeutic Target

Gelsolin, an actin-depolymerizing protein expressed both in extracellular fluids and in the cytoplasm of a majority of human cells, has been recently implicated in a variety of both physiological and pathological processes. Its extracellular isoform, called plasma gelsolin (pGSN), is present in blood, cerebrospinal fluid, milk, urine, and other extracellular fluids. This isoform has been recognized as a potential biomarker of inflammatory-associated medical conditions, allowing for the prediction of illness severity, recovery, efficacy of treatment, and clinical outcome. A compelling number of animal studies also demonstrate a broad spectrum of beneficial effects mediated by gelsolin, suggesting therapeutic utility for extracellular recombinant gelsolin. In the review, we summarize the current data related to the potential of pGSN as an inflammatory predictor and therapeutic target, discuss gelsolin-mediated mechanisms of action, and highlight recent progress in the clinical use of pGSN

Pseudomonas aeruginosa Infections in Cancer Patients

Pseudomonas aeruginosa (P. aeruginosa) is one of the most frequent opportunistic microorganisms causing infections in oncological patients, especially those with neutropenia. Through its ability to adapt to difficult environmental conditions and high intrinsic resistance to antibiotics, it successfully adapts and survives in the hospital environment, causing sporadic infections and outbreaks. It produces a variety of virulence factors that damage host cells, evade host immune responses, and permit colonization and infections of hospitalized patients, who usually develop blood stream, respiratory, urinary tract and skin infections. The wide intrinsic and the increasing acquired resistance 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-&beta;-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

Use of ceragenins as a potential treatment for urinary tract infections

Abstract Background Urinary tract infections (UTIs) are one of the most common bacterial infections. High recurrence rates and the increasing antibiotic resistance among uropathogens constitute a large social and economic problem in current public health. We assumed that combination of treatment that includes the administration ceragenins (CSAs), will reinforce the effect of antimicrobial LL-37 peptide continuously produced by urinary tract epithelial cells. Such treatment might be an innovative approach to enhance innate antibacterial activity against multidrug-resistant E. coli. Methods Antibacterial activity measured using killing assays. Biofilm formation was assessed using crystal violet staining. Viability of bacteria and bladder epithelial cells subjected to incubation with tested agents was determined using MTT assays. We investigated the effects of chosen molecules, both alone and in combinations against four clinical strains of E. coli, obtained from patients diagnosed with recurrent UTI. Results We observed that the LL-37 peptide, whose concentration increases at sites of urinary infection, exerts increased bactericidal effect against E. coli when combined with ceragenins CSA-13 and CSA-131. Conclusion We suggest that the employment of combination of natural peptide LL-37 with synthetic analogs might be a potential solution to treat urinary tract infections caused by drug-resistant bacteria

Extracellular DNA as an essential component and therapeutic target of microbial biofilm

The dominant part of human infections is associated with biofilm formations. Biofilm represents structured communities of bacterial or fungal cells enclosed in self-produced polymeric matrixes adherent to supporting surfaces. Microbial DNA and the host cell DNA, after their release at the infection site, show the ability to promote biofilm formation. Between the different constituents of biofilm matrixes, extracellular DNA (eDNA) may be the only component indispensable for the initial attachment and early biofilm formation through an enhanced matrix structural integrity. The effect of DNA on bacterial/fungal attachment is non-specific, as indicated by the stimulatory effect of plasmid, chromosome, or eukaryotic DNA. DNase I impaired bacterial biofilm growth and the targeting eDNA were recently proposed to eliminate and/or prevent different microbial infections associated with biofilm formations

Neutrophil extracellular traps as the main source of eDNA

Neutrophil extracellular traps (NETs) are web-like structures consisting of decondensed DNA together with accompanying proteins, including histones and antimicrobial peptides released from activated neutrophils as part of the first-line defence against pathogens. Despite the protective role of neutrophils, a number of studies indicate that overproduction of NETs followed by accumulation of extracellular DNA (eDNA) and other negatively-charged polyelectrolytes (PE) such as F-actin, contribute to the pathogenesis of some diseases. Neutrophil extracellular traps are also recognised as the structural and functional support of microbial biofilms and should thus be considered as therapeutic targets. Importantly, the chemical nature of PE permits aggregate formation induced by a number of polycations occurring naturally in the human body, including cationic antimicrobial peptides. This review summarises recent reports focused on the clinical significance of NET-derived eDNA and PE and discusses the potential therapeutic strategies to limit the negative consequences of eDNA accumulation

Defective Sphingolipids Metabolism and Tumor Associated Macrophages as the Possible Links Between Gaucher Disease and Blood Cancer Development

There is a rising number of evidence indicating the increased risk of cancer development in association with congenital metabolic errors. Although these diseases represent disorders of individual genes, they lead to the disruption of metabolic pathways resulting in metabolite accumulation or their deficiency. Gaucher disease (GD) is an autosomal recessive sphingolipidosis. It is a rare lysosomal storage disease. A strong correlation between GD and different types of cancers, such as multiple myeloma, leukemia, and hepatocellular carcinoma, has been reported. Common features for all types of GD include spleen and liver enlargement, cytopenia, and a variety of bone defects. Overall, the molecular bases leading to the association of GD and cancers are not clearly understood. Here, we describe the role of ceramides in GD, discuss the potential implications of immune cells activation and show how the disturbances in their metabolism might promote blood cancer development

Targeting the Gut Microbiota to Relieve the Symptoms of Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a common, chronic, functional disorder with a large impact on world population. Its pathophysiology is not completely revealed; however, it is certain that dysregulation of the bidirectional communications between the central nervous system (CNS) and the gut leads to motility disturbances, visceral hypersensitivity, and altered CNS processing characterized by differences in brain structure, connectivity and functional responsiveness. Emerging evidence suggests that gut microbiota exerts a marked influence on the host during health and disease. Gut microbiome disturbances can be also important for development of IBS symptoms and its modulation efficiently contributes to the therapy. In this work, we review the current knowledge about the IBS therapy, the role of gut microbiota in pathogenesis of IBS, and we discuss that its targeting may have significant impact on the effectiveness of IBS therapy

Sphingosine-1-Phosphate Metabolism and Its Role in the Development of Inflammatory Bowel Disease

Beyond their role as structural molecules, sphingolipids are involved in many important cellular processes including cell proliferation, apoptosis, inflammation, and migration. Altered sphingolipid metabolism is observed in many pathological conditions including gastrointestinal diseases. Inflammatory bowel disease (IBD) represents a state of complex, unpredictable, and destructive inflammation of unknown origin within the gastrointestinal tract. The mechanisms explaining the pathophysiology of IBD involve signal transduction pathways regulating gastro-intestinal system’s immunity. Progressive intestinal tissue destruction observed in chronic inflammation may be associated with an increased risk of colon cancer. Sphingosine-1-phosphate (S1P), a sphingolipid metabolite, functions as a cofactor in inflammatory signaling and becomes a target in the treatment of IBD, which might prevent its conversion to cancer. This paper summarizes new findings indicating the impact of (S1P) on IBD development and IBD-associated carcinogenesis