Resistance of microorganisms to antibiotics has led to research on various therapeutic strategies with different mechanisms of action, including photodynamic inactivation (PDI). In this work, we evaluated a cationic, neutral, and anionic meso-tetraphenylporphyrin derivative’s ability to inactivate the Gram-negative and Gram-positive bacteria in a planktonic suspension under blue light irradiation. The spectroscopic, physicochemical, redox properties, as well as reactive oxygen species (ROS) generation capacity by a set of photosensitizers varying in lipophilicity were investigated. The theoretical calculations were performed to explain the distribution of the molecular charges in the evaluated compounds. Moreover, logP partition coefficients, cellular uptake, and phototoxicity of the photosensitizers towards bacteria were determined. The role of a specific microbial efflux pump inhibitor, verapamil hydrochloride, in PDI was also studied. The results showed that E. coli exhibited higher resistance to PDI than S. aureus (3–5 logs) with low light doses (1–10 J/cm²). In turn, the prolongation of irradiation (up to 100 J/cm²) remarkably improved the inactivation of pathogens (up to 7 logs) and revealed the importance of photosensitizer photostability. The PDI potentiation occurs after the addition of KI (more than 3 logs extra killing). Verapamil increased the uptake of photosensitizers (especially in E. coli) due to efflux pump inhibition. This effect suggests that PDI is mediated by ROS, the electrostatic charge interaction, and the efflux of photosensitizers (PSs) regulated by multidrug-resistance (MDR) systems. Thus, MDR inhibition combined with PDI gives opportunities to treat more resistant bacteria.

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.

Antibiotic resistance represents a pressing global health challenge, now acknowledged as a critical concern within the framework of One Health. Photodynamic inactivation of microorganisms (PDI) offers an attractive, non-invasive approach known for its flexibility, independence from microbial resistance patterns, broad-spectrum efficacy, and minimal risk of inducing resistance. Various photosensitizers, including porphyrin derivatives have been explored for pathogen eradication. In this context, we present the synthesis, spectroscopic and photophysical characteristics as well as antimicrobial properties of a palladium(II)-porphyrin derivative (PdF₂POH), along with its zinc(II)- and free-base counterparts (ZnF₂POH and F₂POH, respectively). Our findings reveal that the palladium(II)-porphyrin complex can be classified as an excellent generator of reactive oxygen species (ROS), encompassing both singlet oxygen (Φ_△ = 0.93) and oxygen-centered radicals. The ability of photosensitizers to generate ROS was assessed using a variety of direct (luminescence measurements) and indirect techniques, including specific fluorescent probes both in solution and in microorganisms during the PDI procedure. We investigated the PDI efficacy of F₂POH, ZnF₂POH, and PdF₂POH against both Gram-negative and Gram-positive bacteria. All tested compounds proved high activity against Gram-positive species, with PdF₂POH exhibiting superior efficacy, leading to up to a 6-log reduction in S. aureus viability. Notably, PdF₂POH-mediated PDI displayed remarkable effectiveness against S. aureus biofilm, a challenging target due to its complex structure and increased resistance to conventional treatments. Furthermore, our results show that PDI with PdF₂POH is more selective for bacterial than for mammalian cells, particularly at lower light doses (up to 5 J/cm² of blue light illumination). This enhanced efficacy of PdF₂POH-mediated PDI as compared to ZnF₂POH and F₂POH can be attributed to more pronounced ROS generation by palladium derivative via both types of photochemical mechanisms (high yields of singlet oxygen generation as well as oxygen-centered radicals). Additionally, PDI proved effective in eliminating bacteria within S. aureus-infected human keratinocytes, inhibiting infection progression while preserving the viability and integrity of infected HaCaT cells. These findings underscore the potential of metalloporphyrins, particularly the Pd(II)-porphyrin complex, as promising photosensitizers for PDI in various bacterial infections, warranting further investigation in advanced infection models. Graphical abstract

Diabetes, and several diseases related to diabetes, including cancer, cardiovascular diseases and neurological disorders, represent one of the major ongoing threats to human life, becoming a true pandemic of the 21st century. Current treatment strategies for diabetes mainly involve promoting β-cell differentiation, and one of the most widely studied targets for β-cell regeneration is DYRK1A kinase, a member of the DYRK family. DYRK1A has been characterized as a key regulator of cell growth, differentiation, and signal transduction in various organisms, while further roles and substrates are the subjects of extensive investigation. The targets of interest in this review are implicated in the regulation of β-cells through DYRK1A inhibition—through driving their transition from highly inefficient and death-prone populations into efficient and sufficient precursors of islet regeneration. Increasing evidence for the role of DYRK1A in diabetes progression and β-cell proliferation expands the potential for pharmaceutical applications of DYRK1A inhibitors. The variety of new compounds and binding modes, determined by crystal structure and in vitro studies, may lead to new strategies for diabetes treatment. This review provides recent insights into the initial self-activation of DYRK1A by tyrosine autophosphorylation. Moreover, the importance of developing novel DYRK1A inhibitors and their implications for the treatment of diabetes are thoroughly discussed. The evolving understanding of DYRK kinase structure and function and emerging high-throughput screening technologies have been described. As a final point of this work, we intend to promote the term “diabetic kinome” as part of scientific terminology to emphasize the role of the synergistic action of multiple kinases in governing the molecular processes that underlie this particular group of diseases.

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.

This study reports the synthesis, characterization, and biological evaluation of four novel heteronuclear Ru(II)-Cu(II) complexes with phosphine-fluoroquinolone conjugates. Structural analysis using X-ray diffraction, density functional theory calculations, and various spectroscopic techniques confirmed the stability and coordination geometries. The cytotoxicity was evaluated in vitro across multiple cancer cell lines (lung, breast, pancreatic, prostate) and noncancerous cells. In vivo toxicity was also assessed using a zebrafish (Danio rerio) larvae model. The results demonstrated that Ru(II)-Cu(II) complexes exhibit greater anticancer activity compared with cisplatin while almost being nontoxic toward control cells in vitro. Mechanistic studies revealed that their action involves nuclei accumulation, reactive oxygen species generation, lipid peroxidation, and mitochondrial membrane depolarization. The expression ratio of Bax to Bcl-2 mRNA correlates with apoptotic cell death. Additionally, encapsulation of the one Ru(II)-Cu(II) complex in bilosomes significantly improved its stability, selectivity, and therapeutic efficacy in three-dimensional (3D) cancer spheroid models.