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Abstract The selective inhibition of kinases from the diabetic kinome is known to promote the regeneration of beta cells and provide an opportunity for the curative treatment of diabetes. The effect can be achieved by carefully tailoring the selectivity of inhibitor toward a particular kinase, especially DYRK1A, previously associated with Down syndrome and Alzheimer's disease. Recently DYRK1A inhibition has been shown to promote both insulin secretion and beta cells proliferation. Here, we show that commonly available flavones are effective inhibitors of DYRK1A. The observed biochemical activity of flavone compounds is confirmed by crystal structures solved at 2.06 Å and 2.32 Å resolution, deciphering the way inhibitors bind in the ATP-binding pocket of the kinase, which is driven by the arrangement of hydroxyl moieties. We also demonstrate antidiabetic properties of these biomolecules and prove that they could be further improved by therapy combined with TGF-β inhibitors. Our data will allow future structure-based optimization of the presented scaffolds toward potent, bioavailable and selective anti-diabetic drugs.

Modern production of vegetable oils has reached impressive levels, and the ever-growing quantities of waste cooking oil (WCO) provide a local source of raw materials for innovative materials. The WCO composite production process involves a series of reactions, including polymerisation, esterification, and transesterification, which lead to the hardening of composite materials. In light of the growing problem of bacterial and fungal diseases, materials with high strength properties and biocidal properties are being sought. Fungal infections of the skin are a widespread problem, and the number of cases is steadily increasing. This article presents a study of the antibacterial potential of WCO-based composites enriched with hops or sorrel root in the context of their application in the construction industry. The compressive and flexural strength of the oil composites, their absorbability and hydrophobicity, and their effects on Gram-positive (S. aureus and S. epidermidis) and Gram-negative (E. coli and P. aeruginosa) bacteria and fungi (A. niger, P. anomala) were investigated. Maximum split tensile strength (4.3 MPa) and flexural strength (5.1 MPa) were recorded for oil-hop composites. Oil composites enriched with curly sorrel and hops showed antibacterial activity against S. aureus at 27% and 25%. High biocidal activity (up to 70%) was recorded against E. coli and against S. epidermidis (up to 99%) due to the action of composites with curly sorrel. The antifungal activities of composites with hops was 15% and 19% for P. anomala and A. niger, respectively, while with curly sorrel they were 42% and 30%.

The decreased β-cell mass and impaired β-cell functionality are the primary causes of diabetes mellitus (DM). Nevertheless, the underlying molecular mechanisms by which β-cell growth and function are controlled are not fully understood. In this work, we show that leucettines, known to be DYRK1A kinase inhibitors, can improve glucose-stimulated insulin secretion (GSIS) in rodent β-cells and isolated islets, as well as in hiPSC-derived β-cells islets. We confirm that DYRK1A is expressed in murine insulinoma cells MIN6. In addition, we found that treatment with selected leucettines stimulates proliferation of β-cells and promotes MIN6 cell cycle progression to the G2/M phase. This effect is also confirmed by increased levels of cyclin D1, which is highly responsive to proliferative signals. Among other leucettines, leucettine L43 had a negligible impact on β-cell proliferation, but markedly impair GSIS. However, leucettine L41, in combination with LY364947, a, a potent and selective TGF-β type-I receptor, significantly promotes GSIS in various cellular diabetic models, including MIN6 and INS1E cells in 2D and 3D culture, iPSC-derived β-cell islets derived from iPSC, and isolated mouse islets, by increased insulin secretion and decreased glucagon level. Our findings confirm an important role of DYRK1A inhibitors as modulators of β-cells function and suggested a new potential target for antidiabetic therapy. Moreover, we show in detail that leucettine derivatives represent promising antidiabetic agents and are worth further evaluation, especially in vivo.

A comprehensive photoluminescence and mechanoluminescence analysis of a ZnS:Mn2+ nano-phosphor with a zinc blende structure is presented. The sample containing quantum dot-sized nanocrystallites was synthesized by the chemical precipitation method and shows excellent orange luminescence at ambient conditions related to the 4T1 → 6A1 transition. The sample shows stable and identical luminescence behavior under both UV and X-ray excitation at ambient conditions and also exhibits excellent self-powered mechanoluminescence properties. The pressure and temperature-induced luminescence mechanism of the phosphor is also established. The shift of the 4T1 → 6A1 luminescence band of Mn2+ with both pressure and temperature and the luminescence mechanism is explained via the d5 Tanabe Sugano diagram. The broad luminescence band of the 4T1 → 6A1 transition shifts from the visible to near-infrared range at a rate of −35.8 meV GPa−1 with the increase of the pressure and it is subsequently quenched completely at a pressure of 16.41 GPa due to a reversible phase transition from zinc blende (F4¯3m) to rocksalt (Fm3¯m) phase. The high-pressure and temperature-dependent decay kinetics measurements of the sample luminescence are also reported. [ABSTRACT FROM AUTHOR]

Two novel phosphine ligands, Ph2PCH2N(CH2CH3)3 (1) and Ph2PCH2N(CH2CH2CH2CH3)2 (2), and six new metal (Cu(I), Ir(III) and Ru(II)) complexes with those ligands: iridium(III) complexes: Ir(η5-Cp*)Cl2(1) (1a), Ir(η5-Cp*)Cl2(2) (2a) (Cp*: Pentamethylcyclopentadienyl); ruthenium(II) complexes: Ru(η6-p-cymene)Cl2(1) (1b), Ru(η6-p-cymene)Cl2(2) (2b) and copper(I) complexes: [Cu(CH3CN)2(1)BF4] (1c), [Cu(CH3CN)2(2)BF4] (2c) were synthesized and characterized using elemental analysis, NMR spectroscopy, and ESI-MS spectrometry. Copper(I) complexes turned out to be highly unstable in the presence of atmospheric oxygen in contrast to ruthenium(II) and iridium(III) complexes. The studied Ru(II) and Ir(III) complexes exhibited promising cytotoxicity towards cancer cells in vitro with IC50 values significantly lower than that of the reference drug—cisplatin. Confocal microscopy analysis showed that Ru(II) and Ir(III) complexes effectively accumulate inside A549 cells with localization in cytoplasm and nuclei. A precise cytometric analysis provided clear evidence for the predominance of apoptosis in induced cell death. Furthermore, the complexes presumably induce the changes in the cell cycle leading to G2/M phase arrest in a dose-dependent manner. Gel electrophoresis experiments revealed that Ru(II) and Ir(III) inorganic compounds showed their unusual low genotoxicity towards plasmid DNA. Additionally, metal complexes were able to generate reactive oxygen species as a result of redox processes, proved by gel electrophoresis and cyclic voltamperometry. In vitro cytotoxicity assays were also carried out within multicellular tumor spheroids and efficient anticancer action on these 3D assemblies was demonstrated. It was proven that the hydrocarbon chain elongation of the phosphine ligand coordinated to the metal ions does not influence the cytotoxic effect of resulting complexes in contrast to metal ions type.

The rising prevalence of diabetes is threatening global health. It is known not only for the occurrence of severe complications but also for the SARS-Cov-2 pandemic, which shows that it exacerbates susceptibility to infections. Current therapies focus on artificially maintaining insulin homeostasis, and a durable cure has not yet been achieved. We demonstrate that our set of small molecule inhibitors of DYRK1A kinase potently promotes β-cell proliferation, enhances long-term insulin secretion, and balances glucagon level in the organoid model of the human islets. Comparable activity is seen in INS-1E and MIN6 cells, in isolated mice islets, and human iPSC-derived β-cells. Our compounds exert a significantly more pronounced effect compared to harmine, the best-documented molecule enhancing β-cell proliferation. Using a body-like environment of the organoid, we provide a proof-of-concept that small–molecule–induced human β-cell proliferation via DYRK1A inhibition is achievable, which lends a considerable promise for regenerative medicine in T1DM and T2DM treatment.

This paper presents the results of the synthesis temperature on the properties of the ceramic powders of SrSi2O2N2:Eu2+ obtained by the solid-phase reaction. Synthesis was carried out in the temperature range of 1250-1650°C for 2 hours in nitrogen flow in the reducing atmosphere of the graphite furnace. The phases present in the resultant powders were identified by X-ray structural analysis (XRD). Scanning electron microscopy (SEM) was used to examine the changes in the powder morphology as a result of the synthesis. The excitation and emission spectra measurements let to study phosphor photoluminescence properties. The results show the strong influence of temperature synthesis on the formation and purity of expected phases. The synthesis temperature also affects the luminescent properties of SrSi2O2N2:Eu2+ ceramic powders.

A series of strontium orthotitanate (Sr2TiO4) samples doped with 2% of a mole of europium, praseodymium, and erbium were obtained using the solid-state synthesis method. The X-ray diffraction (XRD) technique confirms the phase purity of all samples and the lack of the influence of dopants at a given concentration on the structure of materials. The optical properties indicate, in the case of Sr2TiO4:Eu3+, two independent emission (PL) and excitation (PLE) spectra attributed to the Eu3+ ions at sites with different symmetries: low – excited at 360 nm and high – excited at 325 nm, while, for Sr2TiO4:Er3+ and Sr2TiO4:Pr3+, the emission spectra do not depend on the excitation wavelength. The measurements of X-ray photoemission spectroscopy (XPS) indicate the presence of only one type of charge compensation mechanism, which is based on the creation of strontium vacancies in all cases. This suggests that the different charge compensation mechanisms cannot easily explain the presence of Eu3+ at two non-equivalent crystal sites. The photocurrent excitation (PCE) spectroscopy investigations, that have not been reported in the literature so far, show that among all the studied dopants, only Pr3+ can promote the electrons to the conduction band and give rise to electron conductivity. The results collected from the PLE and PCE spectra allowed us to find the location of the ground states of lanthanides(II)/(III) in the studied matrix. [ABSTRACT FROM AUTHOR]

The phosphor powders of Ca(m/2)−xEuxSi12−(m+n)Alm+nOnN16−n (m = 1.6, n = 0.8, x in the range of 0–0.08) were synthesized by means of a solid state reaction in flowing nitrogen in a carbon resistant furnace and the influence of Eu concentration on the crystal structure and photoluminescent properties was thoroughly studied. The optical properties of selected α-sialon:Eu2+ samples at temperatures in the range of 10 to 500 K and pressures up to 240 kbar are presented. The crystal lattice parameters were affected by doping with europium and some increase of the unit cell volume was observed up to 6 mol % of Eu. The higher concentration of europium led to subtle changes in the overall structure of the produced sialon phosphors. It was shown that the chemical composition of Ca, Eu-α-sialon phosphor was slightly different from the designed one and the phosphor powders were contaminated by AlN. The phosphor particle surface showed significant europium and oxygen enrichment with Eu3+ but below the thin surface layer Eu2+ was dominant and higher nitrogen content was observed. After examination of absorption, excitation, and emission spectra it was found that the emission peak position shifted toward longer wavelengths with rising Eu2+ concentration from 565 nm (0.1 mol % Eu2+) to 585 nm (10 mol % Eu2+). The quantum yield of the phosphors reached the maximum at a rather low concentration of 4 mol % of Eu. Excitation spectra depend on the monitored wavelength which is typical for multisite Eu2+. The existence of many Eu2+ sites in the sample was supported by the dependence of the decay time on the monitored wavelength.