80 research outputs found
Lipophilicity of bacteriochlorin-based photosensitizers as a determinant for PDT optimization through the modulation of the inflammatory mediators
Photodynamic therapy (PDT) augments the host antitumor immune response, but the role of the PDT effect on the tumor microenvironment in dependence on the type of photosensitizer and/or therapeutic protocols has not been clearly elucidated. We employed three bacteriochlorins (F2BOH, F2BMet and Cl2BHep) of different polarity that absorb near-infrared light (NIR) and generated a large amount of reactive oxygen species (ROS) to compare the PDT efficacy after various drug-to-light intervals: 15 min. (V-PDT), 3h (E-PDT) and 72h (C-PDT). We also performed the analysis of the molecular mechanisms of PDT crucial for the generation of the long-lasting antitumor immune response. PDT-induced damage affected the integrity of the host tissue and developed acute (protocol-dependent) local inflammation, which in turn led to the infiltration of neutrophils and macrophages. In order to further confirm this hypothesis, a number of proteins in the plasma of PDT-treated mice were identified. Among a wide range of cytokines (IL-6, IL-10, IL-13, IL-15, TNF-α, GM-CSF), chemokines (KC, MCP-1, MIP1α, MIP1β, MIP2) and growth factors (VEGF) released after PDT, an important role was assigned to IL-6. PDT protocols optimized for studied bacteriochlorins led to a significant increase in the survival rate of BALB/c mice bearing CT26 tumors, but each photosensitizer (PS) was more or less potent, depending on the applied DLI (15 min, 3 h or 72 h). Hydrophilic (F2BOH) and amphiphilic (F2BMet) PSs were equally effective in V-PDT (>80 cure rate). F2BMet was the most efficient in E-PDT (DLI = 3h), leading to a cure of 65 % of the animals. Finally, the most powerful PS in the C-PDT (DLI = 72 h) regimen turned out to be the most hydrophobic compound (Cl2BHep), allowing 100 % of treated animals to be cured at a light dose of only 45 J/cm2
Photodynamic inactivation of bacteria with porphyrin derivatives : effect of charge, lipophilicity, ROS generation, and cellular uptake on their biological activity in vitro
Dihydroxyanthraquinones as stable and cost-effective photosensitizers for environmental and biomedical applications
Effects of photodynamic therapy with redaporfin on tumor oxygenation and blood flow in a lung cancer mouse model
Surface modification of nanocrystalline materials with sulfonated porphyrins for visible light antimicrobial therapy
Highly-active, surface-modified anatase TiO2 nanoparticles were successfully synthesized and characterized. The morphological and optical properties of the obtained (metallo)porphyrin@qTiO2 materials were evaluated using absorption and fluorescence spectroscopy, scanning electron microscopy (SEM) imaging, and dynamic light scattering (DLS). These hybrid nanoparticles efficiently generated reactive oxygen species (ROS) under blue-light irradiation (420 ± 20 nm) and possessed a unimodal size distribution of 20–70 nm in diameter. The antimicrobial performance of the synthetized agents was examined against Gram-negative and Gram-positive bacteria. After a short-term incubation of microorganisms with nanomaterials (at 1 g/L) and irradiation with blue-light at a dose of 10 J/cm2, 2–3 logs of Escherichia coli, and 3–4 logs of Staphylococcus aureus were inactivated. A further decrease in bacteria viability was observed after potentiation photodynamic inactivation (PDI), either by H2O2 or KI, resulting in complete microorganism eradication even when using low material concentration (from 0.1 g/L). SEM analysis of bacteria morphology after each mode of PDI suggested different mechanisms of cellular disruption depending on the type of generated oxygen and/or iodide species. These data suggest that TiO2-based materials modified with sulfonated porphyrins are efficient photocatalysts that could be successfully used in biomedical strategies, most notably, photodynamic inactivation of microorganisms
Photoinactivation of microorganisms with sub-micromolar concentrations of imidazolium metallophthalocyanine salts
Study of chemical sympathectomy in endotoxin-induced lethality and fibrin deposition
Study of chemical sympathectomy in endotoxin-induced lethality and fibrin deposition. Shock and the generalized Shwartzman reaction are well known features of endotoxin which have been shown to involve the sympathetic nervous system. The mechanism of sympathetic nervous system involvement with endotoxin injection was studied in rabbits chemically sympathectomized with 6-hydroxydopamine. Endotoxin, in doses producing a spectrum of morbidity and mortality in normal rabbits, was administered i.v. to chemically sympathectomized, normal, and unilateral renal surgically sympathectomized animals. Chemical sympathectomy produced a significant depletion of tissue norepinephrine which, in endotoxin recipient animals, was associated with a significantly lower mortality rate and greatly decreased fibrin deposition in the lungs and kidneys, despite intravascular coagulation. Unilateral renal sympathectomy afforded protection to the ipsilateral kidney, but data on mortality and systemic fibrin deposition were similar to those reported for normal rabbits given endotoxin. Six-hydroxydopamine prevents significant tissue injury secondary to endotoxin in this experimental model. In addition, the data provide direct evidence that an intact reactive sympathetic nervous system is essential for development of lethal toxicity and generalized Shwartzman reaction due to endotoxin.Etude de la sympathectomie chimique de la lethalité et des dépôts de fibrine chez animaux qui ont reçu l'endotoxine. Le choc et le phénomène de Schwartzman généralisé sont des conséquences bien connues de l'endotoxine et il a été montré que ces réactions impliquent le systéme nerveux sympathique. Le mécanisme de la mise en jeu du système nerveux sympathique par l'injection d'endotoxine a été étudié chez des lapins ayant subi une sympathectomie chimique par la 6-hydroxydopamine. L'endotoxine, aux doses qui déterminent une morbidité et une mortalité chez les lapins normaux, a été administrée par voie intraveineuse à des animaux normaux, ayant subi une sympathectomie chimique ou ayant subi une sympathectomie rénale, chirurgicale et unilatérale. La sympathectomie chimique a produit une déplétion significative de norépinéphrine tissulaire qui, chez les animaux qui ont reçu l'endotoxine, a été associée à une diminution significative de la mortalité et une diminution importante des dépôts de fibrine dans les poumons et les reins malgré la coagulation intravasculaire. La sympathectomie unilatérale a protégé le rein ipsilatéral mais la mortalité et les dépôts systémiques de fibrine ont été semblables à ceux observés chez les lapins normaux qui ont reçu l'endotoxine. La 6-hydroxydopamine diminue de façon significative les altérations tissulaires secondaires à l'endotoxine dans ce modèle expérimental. De surcroît, ces observations apportent la preuve directe de ce qu'un système nerveux sympathique intact et réactif est essentiel pour l'apparition de la léthalité et du phénomène de Schwartzman généralisé consécutifs à l'endotoxine
Liposomal binuclear Ir(III)–Cu(II) coordination compounds with phosphino-fluoroquinolone conjugates for human prostate carcinoma treatment
[Image: see text] Novel heteronuclear Ir(III)–Cu(II) coordination compounds ([Ir(η(5)-Cp*)Cl(2)Pcfx-Cu(phen)](NO(3))·1.75(CH(3)OH)·0.75(H(2)O) (1), [Ir(η(5)-Cp*)Cl(2)Pnfx-Cu(phen)](NO(3))·1.75(CH(3)OH)·0.75(H(2)O) (2), [Ir(η(5)-Cp*)Cl(2)Plfx-Cu(phen)](NO(3))·1.3(H(2)O)·1.95(CH(3)OH) (3), [Ir(η(5)-Cp*)Cl(2)Psfx-Cu(phen)] (4)) bearing phosphines derived from fluoroquinolones, namely, sparfloxacin (Hsfx), ciprofloxacin (Hcfx), lomefloxacin (Hlfx), and norfloxacin (Hnfx), have been synthesized and studied as possible anticancer chemotherapeutics. All compounds have been characterized by electrospray ionization mass spectrometry (ESI-MS), a number of spectroscopic methods (i.e., IR, fluorescence, and electron paramagnetic resonance (EPR)), cyclic voltammetry, variable-temperature magnetic susceptibility measurements, and X-ray diffractometry. The coordination geometry of Ir(III) in all complexes adopts a characteristic piano-stool geometry with the η(5)-coordinated and three additional sites occupied by two chloride and phosphine ligands, while Cu(II) ions in complexes 1 and 2 form a distorted square-pyramidal coordination geometry, and in complex 3, the coordination geometry around Cu(II) ions is a distorted octahedron. Interestingly, the crystal structure of [Ir(η(5)-Cp*)Cl(2)Plfx-Cu(phen)] features the one-dimensional (1D) metal–organic polymer. Liposomes loaded with redox-active and fluorescent [Ir(η(5)-Cp*)Cl(2)Pcfx-Cu(phen)] (1L) have been prepared to increase water solubility and minimize serious systemic side effects. It has been proven, by confocal microscopy and an inductively coupled plasma mass spectrometry (ICP-MS) analysis, that the liposomal form of compound 1 can be effectively accumulated inside human lung adenocarcinoma and human prostate carcinoma cells with selective localization in nuclei. A cytometric analysis showed dominance of apoptosis over the other cell death types. Furthermore, the investigated nanoformulations induced changes in the cell cycle, leading to S phase arrest in a dose-dependent manner. Importantly, in vitro anticancer action on three-dimensional (3D) multicellular tumor spheroids has been demonstrated
Diabetic Kinome Inhibitors—A New Opportunity for β-Cells Restoration
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
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