Metaloproteinazy jako nowy wskaźnik diagnostyczny nowotworów skóry

Praca recenzowana / peer-reviewed paperRak podstawnokomórkowy jest najczęściej występującym nowotworem skóry u ludzi rasy kaukaskiej. Wywodzi się on z warstwy komórek podstawnych naskórka oraz mieszków włosowych. BCC (basal cell carcinoma) charakteryzuje się powolnym wzrostem, zdolnością do naciekania i niszczenia okolicznych tkanek. Najczęściej nie daje przerzutów, dzięki czemu zakwalifi kowany został do nowotworów miejscowo złośliwych. Najwięcej przypadków raka podstawnokomórkowego odnotowuje się u osób powyżej 60 roku życia. Skumulowana ekspozycja na promieniowanie ultrafioletowe oraz oparzenia słoneczne w okresie dzieciństwa są głównymi czynnikami zwiększającymi ryzyko rozwoju BCC. Kluczową rolę w rozwoju BCC odgrywają mutacje w genie Ras, P53, a także PTCH i SMO, które są głównymi regulatorami ścieżki szlaku sygnałowego Hedgehog. Nie bez znaczenia w aspekcie podjęcia leczenia pacjentów z BCC jest właściwa diagnostyka. Niejednorodność komórek tworzących ogniska przerzutów nowotworowych, zróżnicowane umiejscowienie czy wielkość zmian nowotworowych, pozostająca poza czułością dostępnych metod diagnostyki obrazowej, to cechy rozsianych zmian nowotworowych przyczyniające się do wysokiej umieralności wśród pacjentów onkologicznych. Nasilona miejscowa ekspresja MMPs (matrix metalloproteinases) uważana jest za nowy, istotny czynnik prognostyczny, który może decydować o wdrożeniu leczenia uzupełniającego. Poprawi to znacząco jakość odróżnienia tkanki guza od tkanki prawidłowej, co pozwoli zmniejszyć liczbę wznów nowotworowych. Dowiedzione różnice w zakresie aktywności MMPs pomiędzy tkankami zmienionymi nowotworowo a tkankami prawidłowymi, stają się punktem wyjścia do wyboru testów dla enzymów proteolitycznych, przebiegających równolegle z badaniami histopatologicznymi.Basal cell carcinoma is the most common malignant tumor among Caucasians. BCC rarely methasizes but can be locally invasive and destructive to neighboring tissues. It is composed of cells that arise from the epidermis and its appendages. Basal cell carcinoma is mostly seen in elderly person, especially those over 60 years of age. Its frequency is slightly higher in males than in females. Cumulative UV exposure and severe sunburn during childhood and adolescence are risk factors for basal cell carcinoma. Th e incidents of BCC also increases with Fitzpatrick skin type I and II, fair or red hair, blue eyes, exposures to trivalent arsenic and ionizing radiation. 90% of BCC occurs on sun-exposed areas such as the face, neck, ears and scalp. Tumor suppressor genes and oncogenes are two basis classes of genes that undergo mutations leading to BCC. Disruption of the Hedgehog signaling pathway, Ras genes and p53 supressing functions are the most important in this tumor. It appears as a slowly growing, translucent papule or nodule. It shows a small capillaries fi lled with blood, known as telangiectasia. This painless change is in many cases ignored by patients, what signifi cantly worsens the prognosis for further treatment. Not without signifi cance in the context of medical treatment of patients with BCC is correct diagnosis. Heterogeneity of cells forming metastatic cancer, diff erentiated location or tumor size is out of the sensitivity of diagnostic imaging methods available are the features of diff use malignant contributing to high mortality among cancer patients. Increased local expression of MMPs is considered to be a new important prognostic factor that can decide on the implementation of any therapy. Th is will improve the quality signifi cantly distinguish tumor tissue from normal tissue, which will reduce the recurrence of cancer. Demonstrated diff erences in the activity of MMPs altered between tumor tissue and normal tissue, becomes the starting point for the selection of tests for proteolytic enzymes, running parallel with histopathology

Extreme resistance to Potato virus Y in potato carrying the Rysto gene is mediated by a TIR-NLR immune receptor

Potato virus Y (PVY) is a major potato (Solanum tuberosum L.) pathogen that causes severe annual crop losses worth billions of dollars worldwide. PVY is transmitted by aphids, and successful control of virus transmission requires the extensive use of environmentally damaging insecticides to reduce vector populations. Rysto , from the wild relative S. stoloniferum, confers extreme resistance (ER) to PVY and related viruses and is a valuable trait that is widely employed in potato resistance breeding programmes. Rysto was previously mapped to a region of potato chromosome XII, but the specific gene has not been identified to date. In this study, we isolated Rysto using resistance gene enrichment sequencing (RenSeq) and PacBio SMRT (Pacific Biosciences single-molecule real-time sequencing). Rysto was found to encode a nucleotide-binding leucine-rich repeat (NLR) protein with an N-terminal TIR domain and was sufficient for PVY perception and ER in transgenic potato plants. Rysto -dependent extreme resistance was temperature-independent and requires EDS1 and NRG1 proteins. Rysto may prove valuable for creating PVY-resistant cultivars of potato and other Solanaceae crops

Imidazolidine-4-one derivatives in the search for novel chemosensitizers of Staphylococcus aureus MRSA : synthesis, biological evaluation and molecular modeling studies

A series of amine derivatives of 5-aromatic imidazolidine-4-ones (7–19), representing three subgroups: piperazine derivatives of 5-arylideneimidazolones (7–13), piperazine derivatives of 5-arylideneimidazolidine-2,4-dione (14–16) and primary amines of 5-naphthyl-5-methylimidazolidine-2,4-diones (17–19), was evaluated for their ability to improve antibiotics effectiveness in two strains of Gram-positive Staphylococcus aureus: ATCC 25923 (a reference strain) and MRSA (methicillin resistant S. aureus) HEMSA 5 (a resistant clinical isolate). The latter compounds (17–19) were obtained by 4-step synthesis using Bucherer-Bergs condensation, two-phase bromoalkylation and Gabriel reactions. The naphthalen derivative: (Z)-5-(naphthalen-2-ylmethylene)-2-(piperazin-1-yl)-3H-imidazol-4(5H)-one (10) was the most potent in combination with β-lactam antibiotics and ciprofloxacin against the resistant strain. The high potency to increase efficacy of oxacillin was noted for (Z)-5-(anthracen-10-ylmethylene)-2-(piperazin-1-yl)-3H-imidazol-4(5H)one (12) too. In order to explain the mechanism of action of the compounds 10 and 12, docking studies with the use of crystal structures of a penicillin binding protein (PBP2a) and MecR1 were carried out. Their outcomes suggested that the most probable mechanism of action of the active compounds is the interaction with MecR1. Molecular dynamic experiments performed for the active compounds and compound 13 (structurally similar to 12) supported this hypothesis and provided possible explanation of activity dependencies of the tested compounds in terms of the restoration of antibiotic efficacy in S. aureus MRSA HEMSA 5

Extended analysis of urethral profilometry in women with urinary stress incontinence – preliminary report

Summary Stress urinary incontinence (SUI) is the most common kind of urinary incontinence in women. Treatment efficiency depends on the type of stress urinary incontinence. Objectives: The purpose of the following study was to compare certain urethral profilometry parameters, including additional ones, in women with stress urinary incontinence (type 0) and women categorized as a ‘transitional group’ who were likely to have the mechanism of the intrinsic sphincter deficiency in pathogenesis of SUI. Material and methods: Examinations included 100 patients with diagnosed SUI based on medical history, clinical evaluation, pad test and urodynamic evaluation. Studied population was divided into three groups depending on the presence of leakage and VLPP value in the urodynamic test. The first group consisted of 19 patients with no leakage during urodynamic test (with SUI type 0), the second group (2) comprised 30 patients with VLPP 60-89 cmH20 and the third group included 36 patients with VLPP ≥90 cmH2O. 15 patients with leakage appearing at VLP

Number of circulating pro-angiogenic cells, growth factor and anti-oxidative gene profiles might be altered in type 2 diabetes with and without diabetic foot syndrome

Aims/Introduction. Type 2 diabetes is often complicated by diabetic foot syndrome (DFS). We analyzed the circulating stem cells, growth factor and anti-oxidant gene expression profiles in type 2 diabetes patients without or with different forms of DFS. Materials and Methods. Healthy volunteers (n = 13) and type 2 diabetes patients: (i) without DFS (n = 10); or with (ii) Charcot osteoneuropathy (n = 10); (iii) non-infected (n = 17); (iv) infected (n = 11); and (v) healed ulceration were examined (n = 12). Peripheral blood endothelial progenitor cells (EPC), mesenchymal stem cells (MSC), hematopoietic stem cells (HSC) and very small embryonic-like (VSEL) cells were phenotyped using flow cytometry. Plasma cytokine concentrations and gene expressions in blood cells were measured by Luminex and quantitative real-time polymerase chain reaction assays, respectively. Results. Patients with non-complicated type 2 diabetes showed reduced HMOX1 expression, accompanied by HMOX2 upregulation, and had less circulating EPC, MSC or HSC than healthy subjects. In contrast, VSEL cells were elevated in the type 2 diabetes group. However, subjects with DFS, even with healed ulceration, had fewer VSEL cells, more CD45-CD29+CD90+MSC, and upregulated HMOX1 when compared with the type 2 diabetes group. Patients with Charcot osteopathy had lowered plasma fibroblast growth factor-2. Elevated plasma tumor necrosis factor-α and decreased catalase expression was found in all diabetic patients. Conclusions. Patients with type 2 diabetes and different forms of DFS have an altered number of circulating stem cells. Type 2 diabetes might also be associated with a changed plasma growth factor and anti-oxidant gene expression profile. Altogether, these factors could contribute to the pathogenesis of different forms of DFS

Phenylpiperazine 5,5-dimethylhydantoin derivatives as first synthetic inhibitors of Msr(A) efflux pump in Staphylococcus epidermidis

Herein, 15 phenylpiperazine 3-benzyl-5,5-dimethylhydantoin derivatives (1–15) were screened for modulatory activity towards Msr(A) efflux pump present in S. epidermidis bacteria. Synthesis, crystallographic analysis, biological studies in vitro and structure–activity relationship (SAR) analysis were performed. The efflux pump inhibitory (EPI) potency was determined by employing ethidium bromide accumulation assay in both Msr(A) efflux pump overexpressed (K/14/1345) and deficient (ATCC 12228) S. epidermidis strains. The series of compounds was also evaluated for the capacity to reduce the resistance of K/14/1345 strain to erythromycin, a known substrate of Msr(A). The study identified five strong modulators for Msr(A) in S. epidermidis. The 2,4-dichlorobenzyl-hydantoin derivative 9 was found as the most potent EPI, inhibiting the efflux activity in K/14/1345 at a concentration as low as 15.63 µM. Crystallography-supported SAR analysis indicated structural properties that may be responsible for the activity found. This study identified the first synthetic compounds able to inhibit Msr(A) efflux pump transporter in S. epidermidis. Thus, the hydantoin-derived molecules found can be an attractive group in search for antibiotic adjuvants acting via Msr(A) transporter

Aspects of a Distinct Cytotoxicity of Selenium Salts and Organic Selenides in Living Cells with Possible Implications for Drug Design

Selenium is traditionally considered as an antioxidant element and selenium compounds are often discussed in the context of chemoprevention and therapy. Recent studies, however, have revealed a rather more colorful and diverse biological action of selenium-based compounds, including the modulation of the intracellular redox homeostasis and an often selective interference with regulatory cellular pathways. Our basic activity and mode of action studies with simple selenium and tellurium salts in different strains of Staphylococcus aureus (MRSA) and Saccharomyces cerevisiae indicate that such compounds are sometimes not particularly toxic on their own, yet enhance the antibacterial potential of known antibiotics, possibly via the bioreductive formation of insoluble elemental deposits. Whilst the selenium and tellurium compounds tested do not necessarily act via the generation of Reactive Oxygen Species (ROS), they seem to interfere with various cellular pathways, including a possible inhibition of the proteasome and hindrance of DNA repair. Here, organic selenides are considerably more active compared to simple salts. The interference of selenium (and tellurium) compounds with multiple targets could provide new avenues for the development of effective antibiotic and anticancer agents which may go well beyond the traditional notion of selenium as a simple antioxidant

Aspects of a distinct cytotoxicity of selenium salts and organic selenides in living cells with possible implications for drug design

Selenium is traditionally considered as an antioxidant element and selenium compounds are often discussed in the context of chemoprevention and therapy. Recent studies, however, have revealed a rather more colorful and diverse biological action of selenium-based compounds, including the modulation of the intracellular redox homeostasis and an often selective interference with regulatory cellular pathways. Our basic activity and mode of action studies with simple selenium and tellurium salts in different strains of Staphylococcus aureus (MRSA) and Saccharomyces cerevisiae indicate that such compounds are sometimes not particularly toxic on their own, yet enhance the antibacterial potential of known antibiotics, possibly via the bioreductive formation of insoluble elemental deposits. Whilst the selenium and tellurium compounds tested do not necessarily act via the generation of Reactive Oxygen Species (ROS), they seem to interfere with various cellular pathways, including a possible inhibition of the proteasome and hindrance of DNA repair. Here, organic selenides are considerably more active compared to simple salts. The interference of selenium (and tellurium) compounds with multiple targets could provide new avenues for the development of effective antibiotic and anticancer agents which may go well beyond the traditional notion of selenium as a simple antioxidant

Chalcogen-Varied Imidazolone Derivatives as Antibiotic Resistance Breakers in Staphylococcus aureus Strains

In this study, a search for new therapeutic agents that may improve the antibacterial activity of conventional antibiotics and help to successfully overcome methicillin-resistant Staphylococcus aureus (MRSA) infections has been conducted. The purpose of this work was to extend the scope of our preliminary studies and to evaluate the adjuvant potency of new derivatives in a set of S. aureus clinical isolates. The study confirmed the high efficacy of piperazine derivatives of 5-arylideneimidazol-4-one (7–9) tested previously, and it enabled the authors to identify even more efficient modulators of bacterial resistance among new analogs. The greatest capacity to enhance oxacillin activity was determined for 1-benzhydrylpiperazine 5-spirofluorenehydantoin derivative (13) which, at concentrations as low as 0.0625 mM, restores the effectiveness of β-lactam antibiotics against MRSA strains. In silico studies showed that the probable mechanism of action of 13 is related to the binding of the molecule with the allosteric site of PBP2a. Interestingly, thiazole derivatives tested were shown to act as both oxacillin and erythromycin conjugators in S. aureus isolates, suggesting a complex mode of action (i.e., influence on the Msr(A) efflux pump). This high enhancer activity indicates the high potential of imidazolones to become commercially available antibiotic adjuvants

Selenazolinium Salts as "Small Molecule Catalysts" with High Potency against ESKAPE Bacterial Pathogens

In view of the pressing need to identify new antibacterial agents able to combat multidrug-resistant bacteria, we investigated a series of fused selenazolinium derivatives (1–8) regarding their in vitro antimicrobial activities against 25 ESKAPE-pathogen strains. Ebselen was used as reference compound. Most of the selenocompounds demonstrated an excellent in vitro activity against all S. aureus strains, with activities comparable to or even exceeding the one of ebselen. In contrast to ebselen, some selenazolinium derivatives (1, 3, and 7) even displayed significant actions against all Gram-negative pathogens tested. The 3-bromo-2-(1-hydroxy-1-methylethyl)[1,2]selenazolo[2,3-a]pyridinium chloride (1) was particularly active (minimum inhibitory concentrations, MICs: 0.31–1.24 µg/mL for MRSA, and 0.31–2.48 µg/mL for Gram-negative bacteria) and devoid of any significant mutagenicity in the Ames assay. Our preliminary mechanistic studies in cell culture indicated that their mode of action is likely to be associated with an alteration of intracellular levels of glutathione and cysteine thiols of different proteins in the bacterial cells, hence supporting the idea that such compounds interact with the intracellular thiolstat. This alteration of pivotal cysteine residues is most likely the result of a direct or catalytic oxidative modification of such residues by the highly reactive selenium species (RSeS) employed