Two-channel dansyl/tryptophan emitters with a cholic acid bridge as reporters for local hydrophobicity within supramolecular systems based on bile salts

The aim of the present work is to develop two-channel emitters to probe local hydrophobicity by means of fluorescence quenching within different biomimetic supramolecular environments. To achieve this goal, the dansyl (Dns) and tryptophan (Trp) fluorophores have been covalently attached to cholic acid (CA) in order to ensure simultaneous incorporation of the two emitting units into the same compartment. In principle, the two fluorophores of the synthesized Dns-CA-Trp probes could either exhibit an orthogonal behavior or display excited state interactions. The fluorescence spectra of 3 beta-Dns-CA-Trp showed a residual Trp emission band at ca. 350 nm and an enhanced Dns maximum in the 500-550 nm region. This reveals a partial intramolecular energy transfer, which is consistent with the Dns and Trp singlet energies. Thus, the two photoactive units are not orthogonal; nevertheless, 3 beta-Dns-CA-Trp seems appropriate as a two-channel reporter for the supramolecular systems of interest. Fluorescence quenching of 3 beta-Dns-CA-Trp by iodide (which remains essentially in bulk water) was examined within sodium cholate, sodium taurocholate, sodium deoxycholate and mixed micelles. Interestingly, a decrease in the emission intensity of the two bands was observed with increasing iodide concentrations. The most remarkable effect was observed for mixed micelles, where the quenching rate constants were one order of magnitude lower than in solution. As anticipated, the quenching efficiency by iodide decreased with increasing hydrophobicity of the microenvironment, a trend that can be correlated with the relative accessibility of the probe to the ionic quencher.Financial support from the Spanish Government (CTQ2012-38754-C03-03), Predoctoral FPU fellowship (AP2008-03295), and the Generalitat Valenciana (Prometeo Program) is gratefully acknowledged.Gómez Mendoza, M.; Marín García, ML.; Miranda Alonso, MÁ. (2014). Two-channel dansyl/tryptophan emitters with a cholic acid bridge as reporters for local hydrophobicity within supramolecular systems based on bile salts. Organic and Biomolecular Chemistry. 12(42):8499-8504. https://doi.org/10.1039/c4ob01394hS849985041242Vayá, I., Lhiaubet-Vallet, V., Jiménez, M. C., & Miranda, M. A. (2014). Photoactive assemblies of organic compounds and biomolecules: drug–protein supramolecular systems. Chem. Soc. Rev., 43(12), 4102-4122. doi:10.1039/c3cs60413fGomez-Mendoza, M., Marin, M. L., & Miranda, M. A. (2011). Dansyl Derivatives of Cholic Acid as Tools to Build Speciation Diagrams for Sodium Cholate Aggregation. The Journal of Physical Chemistry Letters, 2(7), 782-785. doi:10.1021/jz200178rGomez-Mendoza, M., Marin, M. L., & Miranda, M. A. (2012). Dansyl-Labeled Cholic Acid as a Tool To Build Speciation Diagrams for the Aggregation of Bile Acids. The Journal of Physical Chemistry B, 116(51), 14776-14780. doi:10.1021/jp308624hWaissbluth, O. L., Morales, M. C., & Bohne, C. (2006). Influence of Planarity and Size on Guest Binding with Sodium Cholate Aggregates. Photochemistry and Photobiology, 82(4), 1030. doi:10.1562/2006-02-14-ra-803Rinco, O., Kleinman, M. H., & Bohne, C. (2001). Reactivity of Benzophones in the Different Binding Sites of Sodium Cholate Aggregates. Langmuir, 17(19), 5781-5790. doi:10.1021/la010526cHofmann, A. F. (1999). The Continuing Importance of Bile Acids in Liver and Intestinal Disease. Archives of Internal Medicine, 159(22), 2647. doi:10.1001/archinte.159.22.2647Nuin, E., Gómez-Mendoza, M., Andreu, I., Marin, M. L., & Miranda, M. A. (2012). New Photoactive Compounds To Probe Cholic Acid and Cholesterol inside Mixed Micelles. Organic Letters, 15(2), 298-301. doi:10.1021/ol303201yHammad, M. ., & Müller, B. . (1998). Increasing drug solubility by means of bile salt–phosphatidylcholine-based mixed micelles. European Journal of Pharmaceutics and Biopharmaceutics, 46(3), 361-367. doi:10.1016/s0939-6411(98)00037-xHammad, M. ., & Müller, B. . (1998). Solubility and stability of tetrazepam in mixed micelles. European Journal of Pharmaceutical Sciences, 7(1), 49-55. doi:10.1016/s0928-0987(98)00006-2Hammad, M. (1998). Solubility and stability of clonazepam in mixed micelles. International Journal of Pharmaceutics, 169(1), 55-64. doi:10.1016/s0378-5173(98)00117-3Hendradi, E., Obata, Y., Isowa, K., Nagai, T., & Takayama, K. (2003). Effect of Mixed Micelle Formulations Including Terpenes on the Transdermal Delivery of Diclofenac. Biological & Pharmaceutical Bulletin, 26(12), 1739-1743. doi:10.1248/bpb.26.1739Parsaee, S., Sarbolouki, M. N., & Parnianpour, M. (2002). In-vitro release of diclofenac diethylammonium from lipid-based formulations. International Journal of Pharmaceutics, 241(1), 185-190. doi:10.1016/s0378-5173(02)00238-7Yu, J., Zhu, Y., Wang, L., Peng, M., Tong, S., Cao, X., … Xu, X. (2010). Enhancement of oral bioavailability of the poorly water-soluble drug silybin by sodium cholate/phospholipid-mixed micelles. Acta Pharmacologica Sinica, 31(6), 759-764. doi:10.1038/aps.2010.55Sznitowska, M., Klunder, M., & Placzek, M. (2008). Paclitaxel Solubility in Aqueous Dispersions and Mixed Micellar Solutions of Lecithin. CHEMICAL & PHARMACEUTICAL BULLETIN, 56(1), 70-74. doi:10.1248/cpb.56.70Nuin, E., Gomez-Mendoza, M., Marin, M. L., Andreu, I., & Miranda, M. A. (2013). Influence of Drug Encapsulation within Mixed Micelles on the Excited State Dynamics and Accessibility to Ionic Quenchers. The Journal of Physical Chemistry B, 117(32), 9327-9332. doi:10.1021/jp404353uCuquerella, M. C., Rohacova, J., Marin, M. L., & Miranda, M. A. (2010). Stereodifferentiation in fluorescence quenching within cholic acid aggregates. Chemical Communications, 46(27), 4965. doi:10.1039/c0cc00176gWu, J., Liu, W., Ge, J., Zhang, H., & Wang, P. (2011). New sensing mechanisms for design of fluorescent chemosensors emerging in recent years. Chemical Society Reviews, 40(7), 3483. doi:10.1039/c0cs00224kBronshtein, I., Afri, M., Weitman, H., Frimer, A. A., Smith, K. M., & Ehrenberg, B. (2004). Porphyrin Depth in Lipid Bilayers as Determined by Iodide and Parallax Fluorescence Quenching Methods and Its Effect on Photosensitizing Efficiency. Biophysical Journal, 87(2), 1155-1164. doi:10.1529/biophysj.104.041434Rohacova, J., Marin, M. L., Martínez-Romero, A., O’Connor, J.-E., Gomez-Lechon, M. J., Donato, M. T., … Miranda, M. A. (2009). Synthesis of new, UV-photoactive dansyl derivatives for flow cytometric studies on bile acid uptake. Organic & Biomolecular Chemistry, 7(23), 4973. doi:10.1039/b912134jFőrster, T. (1959). 10th Spiers Memorial Lecture. Transfer mechanisms of electronic excitation. Discuss. Faraday Soc., 27(0), 7-17. doi:10.1039/df9592700007Eaton, D. F. (1988). Reference materials for fluorescence measurement. 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Molecular and mass spectroscopic analysis of isotopically labeled organic residues

Experimental studies aimed at understanding the evolution of complex organic molecules on interstellar grains were performed. The photolysis of frozen gas mixtures of various compositions containing H2O, CO, NH3, and CH4 was studied. These species were chosen because of their astrophysical importance as deducted from observational as well as theoretical studies of ice mantles on interstellar grains. These ultraviolet photolyzed ices were warmed up in order to produce refractory organic molecules like the ones formed in molecular clouds when the icy mantles are being irradiated and warmed up either by a nearby stellar source or impulsive heating. The laboratory studies give estimates of the efficiency of production of such organic material under interstellar conditions. It is shown that the gradual carbonization of organic mantles in the diffuse cloud phase leads to higher and higher visual absorptivity - yellow residues become brown in the laboratory. The obtained results can be applied to explaining the organic components of comets and their relevance to the origin of life

Radical-mediated dehydrogenation of bile acids by means of hydrogen atom transfer to triplet carbonyls

The aim of the present paper is to explore the potential of radical-mediated dehydrogenation of bile salts (BSs), which is reminiscent of the enzymatic action of hydroxysteroid dehydrogenase enzymes (HSDH). The concept has been demonstrated using triplet carbonyls that can be efficiently generated upon selective UVA-excitation. Hydrogen atom transfer (HAT) from BSs to triplet benzophenone (BP) derivatives gave rise to radicals, ultimately leading to reduction of the BP chromophore with concomitant formation of the oxo-analogs of the corresponding BSs. The direct reactivity of triplet BP with BSs in the initial step was evaluated by determining the kinetic rate constants using laser flash photolysis (LFP). The BP triplet decay was monitored (lambda(max) = 520 nm) upon addition of increasing BS concentrations, and the obtained rate constant values indicated a reactivity of the methine hydrogen atoms in the order of C-3 < C-12 < C-7. The steady-state kinetics of the overall process, monitored through the disappearance of the typical BP absorption band at 260 nm, was much faster under N-2 than under O-2, also supporting the role of the oxygen-quenchable triplet in the dehydrogenation process. Furthermore, irradiation of deaerated aqueous solutions of sodium cholate in the presence of KPMe provided the oxo-analogs, 3[O], 7[O]-CA, 3[O]-CA and 7[O]-CA, arising from the HAT process.Financial support from the Spanish Government (Grants SEV-2012-0267 and CTQ2012-38754-C03-03), Generalitat Valenciana (Prometeo Program) and the Technical University of Valencia (Predoctoral FPI fellowship for P. Miro) is gratefully acknowledged.Miró Richart, P.; Marín García, ML.; Miranda Alonso, MÁ. (2016). Radical-mediated dehydrogenation of bile acids by means of hydrogen atom transfer to triplet carbonyls. Organic and Biomolecular Chemistry. 14(9):2679-2683. https://doi.org/10.1039/c5ob02561cS2679268314

Photoactive bile salts with critical micellar concentration in the micromolar range

The aggregation behavior of bile salts is strongly dependent on the number of hydroxyl groups. Thus, cholic acid (CA), with three hydroxyls, starts forming aggregates at 15 mM, while deoxycholic, chenodeoxycholic or ursodeoxycholic acids, with two hydroxyls, start aggregating at 5-10 mM; for lithocholic acid, with only one hydroxyl group, aggregation is observed at lower concentration (2-3 mM). Here, the singular self-assembling properties of dansyl and naproxen derivatives of CA (3 beta-Dns-CA and 3 beta-NPX-CA, respectively) have been demonstrated on the basis of their photoactive properties. Thus, the emission spectra of 3 beta-Dns-CA registered at increasing concentrations (25-140 mu M) showed a remarkable non-linear enhancement in the emission intensity accompanied by a hypsochromic shift of the maximum and up to a three-fold increase in the singlet lifetime. The inflection point at around 50-70 mu M pointed to the formation of unprecedented assemblies at such low concentrations. In the case of 3 beta-NPX-CA, when the NPX relative triplet lifetime was plotted against concentration, a marked increase (up to two-fold) was observed at 40-70 mu M, indicating the formation of new 3 beta-NPX-CA assemblies at ca. 50 mu M. Additional evidence supporting the formation of new 3 beta-Dns-CA or 3 beta-NPX-CA assemblies at 40-70 mu M was obtained from singlet excited state quenching experiments using iodide. Moreover, to address the potential formation of hybrid assemblies, 1 : 1 mixtures of 3 beta-Dns-CA and 3 beta-NPX-CA (2-60 mu M, total concentration) were subjected to steady-state fluorescence experiments, and their behavior was compared to that of the pure photoactive derivatives. A lower increase in the emission was observed for 3 beta-NPX-CA in the mixture, while a huge increase was experienced by 3 beta-Dns-CA in the same concentration range (up to 60 mu M total). A partial intermolecular energy transfer from NPX to Dns, consistent with their reported singlet energies, was revealed, pointing to the formation of extremely fluorescent hybrid assemblies at 5-10 mu M (total concentration). The morphology of the entities was investigated by means of confocal microscopy. At 90 mu M, 3 beta-Dns-CA showed disperse assemblies in the mu m range.Financial support from the Spanish Government (Grants SEV-2012-0267 and CTQ2012-38754-C03-03) and the Generalitat Valenciana (Prometeo Program) is gratefully acknowledged.Gómez Mendoza, M.; Marín García, ML.; Miranda Alonso, MÁ. (2016). Photoactive bile salts with critical micellar concentration in the micromolar range. Physical Chemistry Chemical Physics. 18(18):12976-12982. https://doi.org/10.1039/c6cp00813eS1297612982181

Topology and excited state multiplicity as controlling factors in the carbazole-photosensitized CPD formation and repair

Photosensitized thyminethymine (ThyThy) formation and repair can be mediated by carbazole (Cbz). The former occurs from the Cbz triplet excited state via energy transfer, while the latter takes place from the singlet excited state via electron transfer. Here, fundamental insight is provided into the role of the topology and excited state multiplicity, as factors governing the balance between both processes. This has been achieved upon designing and synthesizing different isomers of trifunctional systems containing one Cbz and two Thy units covalently linked to the rigid skeleton of the natural deoxycholic acid. The results shown here prove that the Cbz photosensitized dimerization is not counterbalanced by repair when the latter, instead of operating through-space, has to proceed through-bond. © 2022 The Authors. Published by American Chemical Society

Isonitriles as Alkyl Radical Precursors in Visible Light Mediated Hydro- and Deuterodeamination Reactions

Herein, we report the use of isonitriles as alkyl radical precursors in light-mediated hydro- and deuterodeamination reactions. The reaction is scalable, shows broad functional group compatibility and potential to be used in late-stage functionalization. Importantly, the method is general for Cα-primary, Cα-secondary and Cαtertiary alkyl isonitriles. For most examples, high yields were obtained through direct visible-light irradiation of the isonitrile in the presence of a silyl radical precursor. Interestingly, in the presence of an organic photocatalyst (4CzIPN) a dramatic acceleration was observed. Indepth mechanistic studies using UV/Vis absorption, steady-state and time-resolved photoluminescence, and transient absorption spectroscopy suggest that the excited state of 4CzIPN can engage in a single-electron transfer with the isonitrileWe thank the European Research Council (ERC CoG 101002715 SCAN) and Spanish MCIN/AEI/10.13039/ 501100011033 (grant n° PID2019-107380GB-I00 and PID2022-142594NB-I00 to MT, PID2022-141688OB-I00 and PID2020-118593RB-C22 to ML, PID2019-106184GB-I00, PID2022-139318NB I00 and RED2022-134287-T to IF) for financial support. I.Q. and L.N. thank Comunidad de Madrid for a predoctoral fellowship, and M.M. acknowledges Ministerio de Universidades for a FPU fellowship (FPU20/06

Análisis de la dosis glandular media (DGM) y dosis a tiroides (DTHY) en la mastografía

La mastografía analógica es una imagen por rayos X de las glándulas mamarias, cuyo objetivo principal es detectar el cáncer de mama. De acuerdo con Sechopoulos et al.1 se ha determinado que no hay un riesgo de cáncer de tiroides al realizarse la mastografía. Sin embargo, los nódulos tiroideos en las mujeres tie-nen una prevalencia de 67% y han sido una de las preocupaciones, en cuanto a la seguridad al realizarse la mastografía. Por ello, el objetivo del presente traba-jo es determinar el riesgo radiológico. Al comparar la dosis glandular media (DGM), con la dosis en tiroides (DThy) de las mujeres que se realizan la mastografía para la detección de cáncer de mama en las proyec-ciones: cráneo caudal (CC) y medio lateral oblicua (MLO)

Influenza-Associated Disseminated Aspergillosis in a 9-Year-Old Girl Requiring ECMO Support

Nens; Influenza humana; IsavuconazolNiños; Influenza humana; IsavuconazolChildren; Human influenza; IsavuconazoleA previously healthy 9-year-old girl developed fulminant myocarditis due to severe influenza A infection complicated with methicillin-resistant Staphylococcus aureus pneumonia, requiring extracorporeal membrane oxygenation (ECMO) support. Twelve days after admission, Aspergillus fumigatus was isolated in tracheal aspirate, and 12 h later she suddenly developed anisocoria. Computed tomography (CT) of the head showed fungal brain lesions. Urgent decompressive craniectomy with lesion drainage was performed; histopathology found hyphae in surgical samples, culture-positive for Aspergillus fumigatus (susceptible to azoles, echinocandins, and amphotericin B). Extension workup showed disseminated aspergillosis. After multiple surgeries and combined antifungal therapy (isavuconazole plus liposomal amphotericin B), her clinical course was favorable. Isavuconazole therapeutic drug monitoring was performed weekly. Extensive immunological study ruled out primary immunodeficiencies. Fluorine-18 fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) follow-up showed a gradual decrease in fungal lesions. Influenza-associated pulmonary aspergillosis is well-recognized in critically ill adult patients, but pediatric data are scant. Clinical features described in adults concur with those of our case. Isavuconazole, an off-label drug in children, was chosen because our patient had severe renal failure. To conclude, influenza-associated pulmonary aspergillosis is uncommon in children admitted to intensive care for severe influenza, but pediatricians should be highly aware of this condition to enable prompt diagnosis and treatment.This work received no external funding

Obesogenic Lifestyle and Its Influence on Adiposity in Children and Adolescents, Evidence from Mexico

Overweight (OW) and obesity (OB) during childhood/adolescence are major public health problems in Mexico. Several obesogenic lifestyle (OL) risk factors have been identified, but the burden and consequences of them in Mexican children/adolescents remain unclear. The objective of this study was to estimate the prevalence of OL components and describe their relationships with adiposity, and OW/OB. A population-based cross-sectional study of Mexican children/adolescents with nutritional assessment, data collection on daily habits and adiposity as fat-mass index (FMI) by dual-energy X-ray absorptiometry was performed. Individual OL-components: "inactivity," "excessive screen time," "insufficient sleep," "unhealthy-diet", were defined according to non-adherence to previously published healthy recommendations. RESULTS: 1449 subjects were assessed between March 2015 to April 2018. Sixteen percent of subjects had all four OL-components, 40% had three, 35% had two, 9% had one, and 0.5% had none. A cumulative OL score showed a significant dose-response effect with FMI. The combination of inactivity, excessive screen time, and insufficient sleep showed the highest risk association to OW/OB and higher values of FMI. CONCLUSIONS: The prevalence of OL-components was extremely high and associated with increased adiposity and OW/OB. Several interventions are needed to revert this major public health threat