Dynamics of Oxygen-Independent Photocleavage of Blebbistatin as a One-Photon Blue or Two-Photon Near-Infrared Light-Gated Hydroxyl Radical Photocage

Development of versatile, chemically tunable photocages for photoactivated chemotherapy (PACT) represents an excellent opportunity to address the technical drawbacks of conventional photodynamic therapy (PDT) whose oxygen-dependent nature renders it inadequate in certain therapy contexts such as hypoxic tumors. As an alternative to PDT, oxygen free mechanisms to generate cytotoxic reactive oxygen species (ROS) by visible light cleavable photocages are in demand. Here, we report the detailed mechanisms by which the small molecule blebbistatin acts as a one-photon blue light-gated or two-photon near-infrared light-gated photocage to directly release a hydroxyl radical (•OH) in the absence of oxygen. By using femtosecond transient absorption spectroscopy and chemoselective ROS fluorescent probes, we analyze the dynamics and fate of blebbistatin during photolysis under blue light. Water-dependent photochemistry reveals a critical process of water-assisted protonation and excited state intramolecular proton transfer (ESIPT) that drives the formation of short-lived intermediates, which surprisingly culminates in the release of •OH but not superoxide or singlet oxygen from blebbistatin. CASPT2//CASSCF calculations confirm that hydrogen bonding between water and blebbistatin underpins this process. We further determine that blue light enables blebbistatin to induce mitochondria-dependent apoptosis, an attribute conducive to PACT development. Our work demonstrates blebbistatin as a controllable photocage for •OH generation and provides insight into the potential development of novel PACT agents

Performance measures for the Australian construction industry

This study proposed a multidimensional performance measure framework to evaluate the construction industry's performance. This study measured the performance of the Australian construction industry and made international comparison in 41 countries and regions. The results demonstrated that the construction industry plays an important economic role in promoting national economic development.</p

Ultrafast Photoinduced Electron Transfer between Tetramethylrhodamine and Guanosine in Aqueous Solution

Photoinduced electron transfer based fluorescence correlation spectroscopy (PET-FCS) is a powerful tool to study biomolecular processes. However, some questions remain as to how to correctly interpret the PET-FCS data. In this work, we studied the PET process between tetramethylrhodamine and guanosine by means of femtosecond transient absorption spectroscopy. We derived that the charge separation rate is 4.1 × 109 s–1 and the charge recombination rate is 5.2 × 1010 s–1 for the current system, supporting the three-state model and the interpretation on PET-FCS experiments given by Qu et al. (J. Phys Chem. B, 2010, 114, 8235). At the limit that both the charge separation and recombination rates are much faster than the process that PET-FCS reveals, the three-state model can be simplified to an equivalent two-state model with a dark state whose brightness is nonzero. We propose ways to obtain the brightness of the dark state with additional experiments, which is necessary for a PET-FCS study

Singlet versus Triplet Excited State Mediated Photoinduced Dehalogenation Reactions of Itraconazole in Acetonitrile and Aqueous Solutions

Photoinduced dehalogenation of the antifungal drug itraconazole (ITR) in acetonitrile (ACN) and ACN/water mixed solutions was investigated using femtosecond and nanosecond time-resolved transient absorption (fs-TA and ns-TA, respectively) and nanosecond time-resolved resonance Raman spectroscopy (ns-TR³) experiments. An excited resonance energy transfer is found to take place from the 4-phenyl-4,5-dihydro-3<i>H</i>-1,2,4-triazol-3-one part of the molecule to the 1,3-dichlorobenzene part of the molecule when ITR is excited by ultraviolet light. This photoexcitation is followed by a fast carbon–halogen bond cleavage that leads to the generation of radical intermediates via either triplet and/or singlet excited states. It is found that the singlet excited state-mediated carbon–halogen cleavage is the predominant dehalogenation process in ACN solvent, whereas a triplet state-mediated carbon–halogen cleavage prefers to occur in the ACN/water mixed solutions. The singlet-to-triplet energy gap is decreased in the ACN/water mixed solvents and this helps facilitate an intersystem crossing process, and thus, the carbon–halogen bond cleavage happens mostly through an excited triplet state in the aqueous solutions examined. The ns-TA and ns-TR³ results also provide some evidence that radical intermediates are generated through a homolytic carbon–halogen bond cleavage via predominantly the singlet excited state pathway in ACN but via mainly the triplet state pathway in the aqueous solutions. In strong acidic solutions, protonation at the oxygen and/or nitrogen atoms of the 1,2,4-triazole-3-one group appears to hinder the dehalogenation reactions. This may offer the possibility that the phototoxicity of ITR due to the generation of aryl or halogen radicals can be reduced by protonation of certain moieties in suitably designed ITR halogen-containing derivatives

Direct Time-Resolved Spectroscopic Observation of Arylnitrenium Ion Reactions with Guanine-Containing DNA Oligomers

The metabolic activation of a number of aromatic amine compounds to arylnitrenium ions that can react with DNA to form covalent adducts has been linked to carcinogenesis. Guanine in DNA has been shown to be the main target of N-containing carcinogens, and many monomeric guanine derivatives have been utilized as models for product analysis and spectroscopic investigations to attempt to better understand the reaction mechanisms of DNA with arylnitrenium ions. However, there are still important unresolved issues regarding how arylnitrenium ions attack guanine residues in DNA oligomers. In this article, we employed ns-TA and ns-TR³ spectroscopies to directly observe the reaction of the 2-fluorenylnitrenium ion with selected DNA oligomers, and we detected an intermediate possessing a similar C8 structure as the intermediates produced from the reaction of monomeric guanosine derivatives with arylnitrenium ions. Our results suggest that the oligomeric structure can lead to a faster reaction rate of arylnitrenium ions with guanine residues in DNA oligomers and the reaction of arylnitrenium ions take place in a manner similar to reactions with monomeric guanosine derivatives

Polymerization-Induced Self-Assembly Toward Micelle-Crosslinked Tough and Ultrastretchable Hydrogels

As a promising class of tough and ultrastretchable hydrogels, micelle-crosslinked hydrogels have been restrained by the scarcity of micellar crosslinkers with a high concentration, controlled nanostructure, and uniform size distribution. Herein, polymerization-induced self-assembly (PISA) was demonstrated to be a general and powerful platform for micellar crosslinkers, affording micelle-crosslinked hydrogels with tailorable chemical structures, mechanics, and functionality. Poly­(N,N-dimethylacrylamide)-b-poly­(diacetone acrylamide) (PDMAc-b-PDAAM) micellar crosslinkers with a controlled nanostructure and uniform size distribution were prepared via PISA and one-step post-polymerization modification at high concentrations. Copolymerization of these micellar crosslinkers with acrylamide generated tough and ultrastretchable hydrogels, whose mechanical properties were found correlated with the concentration, nanostructure, and chemical composition of the micelles. The energy dissipation mechanism of these micelle-crosslinked hydrogels was analyzed via cyclic mechanical tests and stress relaxation experiments. The general feasibility of PISA toward micelle-crosslinked hydrogels was verified by systematic evaluation of both aqueous (including 2-methoxyethyl acrylate, tetrahydro-2-furanylmethyl acrylate, and 4-hydroxybutyl acrylate) and alcoholic (including benzyl methacrylate, lauryl methacrylate, styrene, and benzyl acrylate) PISA formulations, producing hydrogels with diverse chemical structures, mechanics, and functionalities depending on the micellar crosslinkers. The modularity of this strategy was further demonstrated by the fabrication of fluoro-functionalized hydrogels with fluoro-containing micellar crosslinkers. This strategy has significantly enlarged the scope and application of micelle-crosslinked hydrogels

Image_2_Effect of metformin on sepsis-associated acute lung injury and gut microbiota in aged rats with sepsis.tif

BackgroundRecent studies reported the association between the changes in gut microbiota and sepsis, but there is unclear for the gut microbes on aged sepsis is associated acute lung injury (SALI), and metformin treatment for the change in gut microbiota. This study aimed to investigate the effect of metformin on gut microbiota and SALI in aged rats with sepsis. It also explored the therapeutic mechanism and the effect of metformin on aged rats with SALI.MethodsAged 20-21 months SD rats were categorized into three groups: sham-operated rats (AgS group), rats with cecal ligation and puncture (CLP)-induced sepsis (AgCLP group), and rats treated with metformin (100 mg/kg) orally 1 h after CLP treatment (AgMET group). We collected feces from rats and analyzed them by 16S rRNA sequencing. Further, the lung samples were collected for histological analysis and quantitative real-time PCR (qPCR) assay and so on.ResultsThis study showed that some pathological changes occurring in the lungs of aged rats, such as hemorrhage, edema, and inflammation, improved after metformin treatment; the number of hepatocyte death increased in the AgCLP group, and decreased in the AgMET group. Moreover, metformin relieved SALI inflammation and damage. Importantly, the gut microbiota composition among the three groups in aged SALI rats was different. In particular, the proportion of E. coli and K. pneumoniae was higher in AgCLP group rats than AgS group rats and AgMET group rats; while metformin could increase the proportion of Firmicutes, Lactobacillus, Ruminococcus_1 and Lactobacillus_johnsonii in aged SALI rats. Moreover, Prevotella_9, Klebsiella and Escherichia_Shigella were correlated positively with the inflammatory factor IL-1 in the lung tissues; Firmicutes was correlated negatively with the inflammatory factor IL-1 and IL-6 in the lung tissues.ConclusionsOur findings suggested that metformin could improve SALI and gut microbiota in aged rats, which could provide a potential therapeutic treatment for SALI in aged sepsis.</p

Image_1_Effect of metformin on sepsis-associated acute lung injury and gut microbiota in aged rats with sepsis.tif

BackgroundRecent studies reported the association between the changes in gut microbiota and sepsis, but there is unclear for the gut microbes on aged sepsis is associated acute lung injury (SALI), and metformin treatment for the change in gut microbiota. This study aimed to investigate the effect of metformin on gut microbiota and SALI in aged rats with sepsis. It also explored the therapeutic mechanism and the effect of metformin on aged rats with SALI.MethodsAged 20-21 months SD rats were categorized into three groups: sham-operated rats (AgS group), rats with cecal ligation and puncture (CLP)-induced sepsis (AgCLP group), and rats treated with metformin (100 mg/kg) orally 1 h after CLP treatment (AgMET group). We collected feces from rats and analyzed them by 16S rRNA sequencing. Further, the lung samples were collected for histological analysis and quantitative real-time PCR (qPCR) assay and so on.ResultsThis study showed that some pathological changes occurring in the lungs of aged rats, such as hemorrhage, edema, and inflammation, improved after metformin treatment; the number of hepatocyte death increased in the AgCLP group, and decreased in the AgMET group. Moreover, metformin relieved SALI inflammation and damage. Importantly, the gut microbiota composition among the three groups in aged SALI rats was different. In particular, the proportion of E. coli and K. pneumoniae was higher in AgCLP group rats than AgS group rats and AgMET group rats; while metformin could increase the proportion of Firmicutes, Lactobacillus, Ruminococcus_1 and Lactobacillus_johnsonii in aged SALI rats. Moreover, Prevotella_9, Klebsiella and Escherichia_Shigella were correlated positively with the inflammatory factor IL-1 in the lung tissues; Firmicutes was correlated negatively with the inflammatory factor IL-1 and IL-6 in the lung tissues.ConclusionsOur findings suggested that metformin could improve SALI and gut microbiota in aged rats, which could provide a potential therapeutic treatment for SALI in aged sepsis.</p

Investigation of Ultrafast Configurational Photoisomerization of Bilirubin Using Femtosecond Stimulated Raman Spectroscopy

Phototherapy is an efficient and safe way to reduce high levels of free 4Z,15Z-bilirubin (ZZ-BR) in the serum of newborns. The success of BR phototherapy lies in photoinduced configurational and structural isomerization processes that form excretable isomers. However, the physical picture of photoinduced photoisomerization of ZZ-BR is still unclear. Here, we strategically implement tunable femtosecond stimulated Raman spectroscopy and several time-resolved electronic spectroscopies, assisted by quantum chemical calculations, to dissect the detailed primary configurational isomerization dynamics of free ZZ-BR in organic solvents. The results of this study demonstrate that upon photoexcitation, ultrafast configurational isomerization proceeds by a volume-conserving “hula twist”, followed by intramolecular hydrogen-bond distortion and large-scale rotation of the two dipyrrinone halves of the ZZ-BR isomer in a few picoseconds. After that, most of the population recovers back to ZZ-BR, and a very small amount is converted into stable BR isomers via structural isomerization