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

Impacts of the Tropical Pacific/Indian Oceans on the Seasonal Cycle of the West African Monsoon

The current consensus is that drought has developed in the Sahel during the second half of the twentieth century as a result of remote effects of oceanic anomalies amplified by local land–atmosphere interactions. This paper focuses on the impacts of oceanic anomalies upon West African climate and specifically aims to identify those from SST anomalies in the Pacific/Indian Oceans during spring and summer seasons, when they were significant. Idealized sensitivity experiments are performed with four atmospheric general circulation models (AGCMs). The prescribed SST patterns used in the AGCMs are based on the leading mode of covariability between SST anomalies over the Pacific/Indian Oceans and summer rainfall over West Africa. The results show that such oceanic anomalies in the Pacific/Indian Ocean lead to a northward shift of an anomalous dry belt from the Gulf of Guinea to the Sahel as the season advances. In the Sahel, the magnitude of rainfall anomalies is comparable to that obtained by other authors using SST anomalies confined to the proximity of the Atlantic Ocean. The mechanism connecting the Pacific/Indian SST anomalies with West African rainfall has a strong seasonal cycle. In spring (May and June), anomalous subsidence develops over both the Maritime Continent and the equatorial Atlantic in response to the enhanced equatorial heating. Precipitation increases over continental West Africa in association with stronger zonal convergence of moisture. In addition, precipitation decreases over the Gulf of Guinea. During the monsoon peak (July and August), the SST anomalies move westward over the equatorial Pacific and the two regions where subsidence occurred earlier in the seasons merge over West Africa. The monsoon weakens and rainfall decreases over the Sahel, especially in August.Peer reviewe

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-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

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

Metallic Nanosystems in the Development of Antimicrobial Strategies with High Antimicrobial Activity and High Biocompatibility

Antimicrobial resistance is a major and growing global problem and new approaches to combat infections caused by antibiotic resistant bacterial strains are needed. In recent years, increasing attention has been paid to nanomedicine, which has great potential in the development of controlled systems for delivering drugs to specific sites and targeting specific cells, such as pathogenic microbes. There is continued interest in metallic nanoparticles and nanosystems based on metallic nanoparticles containing antimicrobial agents attached to their surface (core shell nanosystems), which offer unique properties, such as the ability to overcome microbial resistance, enhancing antimicrobial activity against both planktonic and biofilm embedded microorganisms, reducing cell toxicity and the possibility of reducing the dosage of antimicrobials. The current review presents the synergistic interactions within metallic nanoparticles by functionalizing their surface with appropriate agents, defining the core structure of metallic nanoparticles and their use in combination therapy to fight infections. Various approaches to modulate the biocompatibility of metallic nanoparticles to control their toxicity in future medical applications are also discussed, as well as their ability to induce resistance and their effects on the host microbiome

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