Optimal photosensitizers for photodynamic therapy of infections should kill bacteria but spare neutrophils

Photodynamic therapy (PDT) for localized microbial infections exerts its therapeutic effect both by direct bacterial killing and also by the bactericidal effects of host neutrophils stimulated by PDT. Therefore, PDT-induced damage to neutrophils must be minimized, while direct photoinactivation of bacteria is maintained to maximize the therapeutic efficacy of antimicrobial PDT in vivo. However, there has been no study in which the cytocidal effect of PDT on neutrophils was investigated. In this study, the cytocidal effects of PDT on neutrophils were evaluated using different antimicrobial photosensitizers to find suitable candidate photosensitizers for antimicrobial PDT. PDT on murine peripheral-blood neutrophils was performed in vitro using each photosensitizer at a concentration that exerted a maximum bactericidal effect on methicillin-resistant Staphylococcus aureus, and morphological alteration and viability of neutrophils were studied. Most neutrophils were viable (>80%) after PDT using toluidine blue-O (TB) or methylene blue (MB), while neutrophils showed morphological change and their viabilities were decreased (<70%) after PDT using other photosensitizers (erythrosine B, rose bengal, crystal violet, Photofrin, new methylene blue and Laserphyrin). These results suggest that PDT using TB or MB can preserve host neutrophils while exerting a significant therapeutic effect on in vivo localized microbial infection.     

Photo- and thermal curing of tri-functional methacrylate with degradable property

Tri-functional methacrylate (MA3) having thermally degradable tertiary ester linkages was synthesized by a convergent approach. When the MA3 film containing a thermal initiator and a photoacid generator was heated under nitrogen atmosphere, it became insoluble. The thermally cured MA3 became soluble after irradiated and followed by baking at 120 °C. Acid catalyzed decomposition of the tertiary ester linkages of the MA3 moiety occurred at lower temperatures than non-catalyzed one. A mechanism for the photo- or thermal curing and photoassisted-thermal degradation was studied by FT-IR, ¹H NMR, TGA, MS, and SEC analyses.     

New reaction model for O-O bond formation and O2 evolution catalyzed by dinuclear manganese complex

A new mechanism of the oxygen evolving reaction catalyzed by [H(2)O(terpy)Mn(μ-O)(2)Mn(terpy)OH(2)](3+) is proposed by using density functional theory. This proton coupled electron transfer (PCET) model shows reasonable barriers. Because in experiments excess oxidants (OCl(-) or HSO(5)(-)) are required to evolve oxygen from water, we considered the Mn(2) complex neutralized by three counterions. Structure optimization made the coordinated OCl(-) withdraw a H(+) from the water ligand and produces the reaction space for H(2)O(2) formation with the deprotonated OH(-) ligand. The reaction barrier for the H(2)O(2) formation from OH(-) and protonated OCl(-) depends significantly on the system charge and is 14.0 kcal/mol when the system is neutralized. The H(2)O(2) decomposes to O(2) during two PCET processes to the Mn(2) complex, both with barriers lower than 12.0 kcal/mol. In both PCET processes the spin moment of transferred electrons prefers to be parallel to that of Mn 3d electrons because of the exchange interaction. This model thus explains how the triplet O(2) molecule is produced.     

Time-domain observation of the spinmotive force in permalloy nanowires

The spinmotive force associated with a moving domain wall is observed directly in Permalloy nanowires using real time voltage measurements with proper subtraction of the electromotive force. Whereas the wall velocity exhibits nonlinear dependence on magnetic field, the generated voltage increases linearly with the field. We show that the sign of the voltage reverses when the wall propagation direction is altered. Numerical simulations explain quantitatively these features of spinmotive force and indicate that it scales with the field even in a field range where the wall motion is no longer associated with periodic angular rotation of the wall magnetization.     

Biological monitoring of solar UV radiation at 17 sites in Asia, Europe and South America from 1999 to 2004

A small and robust dosimeter for determining the biologically effective dose of ambient UV radiation has been developed using UV-sensitive mutant spores of Bacillus subtilis strain TKJ6312. A membrane filter with four spots of the spores was snapped to a slide mount. The slide was wrapped and covered with two or more layers of polyethylene sheet to protect the sample from rain and snow and to reduce monthly-cumulative doses within the measurable range. From 1999, monthly data were collected at 17 sites for more than 1 year, and data for 4 to 6 consecutive years were obtained from 12 sites. Yearly total values of the spore inactivation dose (SID) ranged from 3200 at subarctic Oulu to 96000 at tropical Denpasar, and the mean yearly values of SID exhibited an exponential dependence on latitude in both hemispheres with a doubling for about every 14 degrees of change. During the observation period, increasing trends of UV doses have been observed at all sites with more than 5 years of data available. Year-to-year variations at high and middle latitude sites are considered due mostly to climatic variation. At three tropical sites, negative correlations between the yearly doses and the column ozone amounts were observed. The results verified the applicability of spore dosimetry for global and long-time monitoring of solar UV radiation, in particular at tropical sites where no monitoring is taking place.     

Linezolid and Vancomycin Decrease the Therapeutic Effect of Methylene Blue‐Photodynamic therapy in a Mouse Model of MRSA Bacterial Arthritis

We previously reported that photodynamic therapy (PDT) using intra‐articular methylene blue (MB) could be used to treat arthritis in mice caused by bioluminescent methicillin‐resistant Staphylococcus aureus (MRSA) either in a therapeutic or in a preventative mode. PDT accumulated neutrophils into the mouse knee via activation of chemoattractants such as inflammatory cytokines or chemokines. In this study, we asked whether PDT combined with antibiotics used for MRSA could provide added benefit in controlling the infection. We compared MB‐PDT alone, systemic administration of either linezolid (LZD) alone or vancomycin (VCM) alone or the combination of PDT with either LZD or VCM. Real‐time noninvasive imaging was used to serially follow the progress of the infection. PDT alone was the most effective, whereas LZD alone was ineffective and VCM alone showed some benefit. Surprisingly the addition of LZD or VCM reduced the therapeutic effect of PDT alone (P < 0.05). Considering that PDT in this mouse model stimulates neutrophils to be antibacterial rather than actively killing the bacteria, we propose that LZD and VCM might inhibit the activation of inflammatory cytokines without eradicating the bacteria, and thereby reduce the therapeutic effect of PDT.     

Oxidation of Sulfides with Hydrogen Peroxide Catalyzed by Vitamin B2 Derivatives

5-Ethyl-3-methyl-2′,4′:3′,5′-di-O-methylenedioxyriboflavinium perchlorate (1, DMRFlEt⁺ClO₄ ^–), derived readily from commercially available vitamin B₂ (riboflavin), exhibits high catalytic activity for the oxidation of organic sulfides with hydrogen peroxide. The reaction provides an efficient and selective method for the oxidative transformation of organic sulfides to the corresponding sulfoxides under mild conditions.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource: Full experimental and spectral details.]     

Effective Extraction of Limonene and Hibaene from Hinoki (Chamaecyparis obtusa) Using Ionic Liquid and Deep Eutectic Solvent

The essential oils of hinoki (Chamaecyparis obtusa) leaves have anti-bacterial, anti-fungal, and relaxation properties that are likely associated with the major components such as sabinene, α-terpinyl acetate, limonene, elemol, myrcene, and hibaene. The present study describes the use of a cellulose-dissolving ionic liquid (IL) [C₂mim][(MeO)(H)PO₂] and low-toxicity solvents called betaine-based deep eutectic solvents (DESs) for the efficient extraction of hinoki essential oils. As a control method, organic solvent extraction was performed using either hexane, ethyl acetate (EtOAc), or acetone at 30 °C for 1 h. Both the experimental and control methods were conducted under the same conditions, which relied on partial dissolution of the leaves using the IL and DESs before partitioning the hinoki oils into the organic solvent for analysis. Quantitative analysis was performed using gas chromatography–mass spectrometry (GC-MS) in selected ion monitoring (SIM) mode. The results indicated that extraction using the [C₂mim][(MeO)(H)PO₂]/acetone bilayer system improved the yields of limonene and hibaene, 1.5- and 1.9-fold, respectively, when compared with the control method. In addition, extraction using betaine/l-lactic acid (molar ratio 1:1) gave the greatest yields for both limonene and hibaene, 1.3-fold and 1.5-fold greater, respectively, than when using an organic solvent. These results demonstrate the effective extraction of essential oils from plant leaves under conditions milder than those needed for the conventional method. The less toxic and environmentally begin DESs for the extraction are also applicable to the food and cosmetic industries.