May Staphylococcus lugdunensis Be an Etiological Factor of Chronic Maxillary Sinuses Infection?

Staphylococcus lugdunensis is an opportunistic pathogen found in the healthy human skin microbiome bacterial community that is able to cause infections of diverse localization, manifestation, and course, including laryngological infections, such as necrotizing sinusitis. Chronic maxillary sinusitis is a disease present in up to one third of European and American populations, and its etiology is not fully described. Within this study, we aimed to characterize 18 S. lugdunensis strains recovered from maxillary sinuses and evaluate them as etiological agents of chronic disease. We performed MLST analysis, the complex analysis of both phenotypic and genetic virulence factors, antibiotic susceptibility profiles, and biofilm formation assay for the detection of biofilm-associated genes. Altogether, S. lugdunensis strains were clustered into eight different STs, and we demonstrated several virulence factors associated with the chronic disease. All tested strains were able to produce biofilm in vitro with numerous strains with a very strong ability, and overall, they were mostly susceptible to antibiotics, although we found resistance to fosfomycin, erythromycin, and clindamycin in several strains. We believe that further in-depth analysis of S. lugdunensis strains from different niches, including the nasal one, should be performed in the future in order to reduce infection rate and broaden the knowledge about this opportunistic pathogen that is gaining attention.     

Preparation of Novel Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides and Their Experimental and Computational Biological Studies

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides constitute a novel class of heterocyclic compounds with broad biological activity, including anticancer properties. Investigated in this study, MM-compounds (MM134, MM136, MM137, and MM139) exhibited cytotoxic and proapoptotic activity against cancer cell lines (BxPC-3, PC-3, and HCT-116) in nanomolar concentrations without causing cytotoxicity in normal cells (L929 and WI38). In silico predictions indicate that tested compounds exhibit favorable pharmacokinetic profiles and may exert anticancer activity through the inhibition of BTK kinase, the AKT-mTOR pathway and PD1-PD-L1 interaction. Our findings point out that these sulfonamide derivatives may constitute a source of new anticancer drugs after optimization.     

Lysosomal Exocytosis of Olivacine on the Way to Explain Drug Resistance in Cancer Cells

Ellipticine is an indole alkaloid with proven antitumor activity against various tumors in vitro and a diverse mechanism of action, which includes topoisomerase II inhibition, intercalation, and cell cycle impact. Olivacine—ellipticine’s isomer—shows similar properties. The objectives of this work were as follows: (a) to find a new path of olivacine synthesis, (b) to study the cytotoxic properties of olivacine and ellipticine in comparison to doxorubicin as well as their impact on the cell cycle, and (c) to investigate the cellular pharmacokinetics of the tested compounds to understand drug resistance in cancer cells better. SRB and MTT assays were used to study the anticancer activity of olivacine and ellipticine in vitro. Both compounds showed a cytotoxic effect on various cell lines, most notably on the doxorubicin-resistant LoVo/DX model, with olivacine’s cytotoxicity approximately three times higher than doxorubicin. Olivacine proved to be less effective against cancer cells and less cytotoxic to normal cells than ellipticine. Olivacine proved to have fluorescent properties. Microscopic observation of cells treated with olivacine showed the difference in sensitivity depending on the cell line, with A549 cells visibly affected by a much lower concentration of olivacine than normal NHDF cells. An increased percentage of cells in G0/G1 was observed after treatment with olivacine and ellipticine, suggesting an impact on cell cycle progression, potentially via higher p53 protein expression, which blocks the transition from G0/G1 to the S phase. Ellipticine induced apoptosis at a concentration as low as 1 μM. It has been proved that the tested compounds (ellipticine and olivacine) undergo lysosomal exocytosis. Reducing exocytosis is possible through the use of compounds that inhibit the activity of the proton pump. Olivacine and ellipticine exhibited diverse cytotoxicity against a panel of cancer cells. Analysis of the lysosomal exocytosis of olivacine and ellipticine shows the need to look for derivatives with comparable anticancer activity but reduced weak base character.     

Design,Synthesis, and Characterization of a Novel Fluoroprobe for Live Human Islet Cell Imaging of Serotonin 5-HT1A Receptor

Mounting evidence suggests that the serotonin system serves in signal transmission to regulate insulin secretion in pancreatic islets of Langerhans. Among the 5-HT receptor subtype found in pancreatic islets, serotonin receptor 1A (5-HT_1A) demonstrates a unique ability to inhibit β-cell insulin secretion. We report the design, synthesis, and characterization of two novel fluorescent probes for the 5-HT_1A receptor. The compounds were prepared by conjugating the scaffold of the 5-HT_1A receptor agonist 8-OH-DPAT with two fluorophores suitable for live-cell imaging. Compound 5a {5-(dimethylamino)-N-[5-[(8-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino]pentyl]naphtalen-1-sulfonammide} showed high affinity for the 5-HT_1A receptor (K_i=1.8 nM). Fluoroprobe 5a was able to label the 5-HT_1A receptor in pancreatic islet cell cultures in a selective manner, as the fluorescence emission was significantly attenuated by co-administration of the 5-HT_1A receptor antagonist WAY-100635. Thus, fluoroprobe 5a showed useful properties to further characterize this unique receptor‘s role.     

Controlling Crystallization: A Key Factor during 3D Printing with the Advanced Semicrystalline Polymeric Materials PEEK,PEKK 6002, and PEKK 7002

Controlling the crystallization of advanced, high-performance polymeric materials during 3D printing is critical to ensure that the resulting structures have appropriate mechanical properties. In this work, two grades of polyetherketoneketone (PEKK 6002 and PEKK 7002) are used to print 3D specimens via a fused filament fabrication process. The samples are compared with polyetheretherketone printed under the same conditions. Two approaches for controlling the crystallization process are undertaken. The first involves adjustment of the chamber temperature between room temperature and 190 °C to create two regions where crystallization is governed by the slow diffusion process and elevated by limiting the nucleation process. The second approach involves selection of PEKK materials with varying crystallization kinetics, namely. Application of this method into 3D-printing process allows for printing semicrystalline materials with tailored mechanical, thermal, and chemical properties as either amorphous or in situ crystallized products. The studies undertaken here provide the basis to eliminate expensive and time-consuming post-processing of 3D fabricated parts. In particular, solutions for the avoidance of poor adhesion to the building plate and weak interlayer adhesion that can lead to warping are described. The materials are divided into three groups, slow, moderate, and too fast crystallization kinetics.