Photooxygenation mechanisms in naproxen-amino acid linked systems

The photooxygenation of model compounds containing the two enantiomers of naproxen (NPX) covalently linked to histidine (His), tryptophan (Trp) and tyrosine (Tyr) has been investigated by steady state irradiation, fluorescence spectroscopy and laser flash photolysis. The NPX–His systems presented the highest oxygen-mediated photoreactivity. Their fluorescence spectra matched that of isolated NPX and showed a clear quenching by oxygen, leading to a diminished production of the NPX triplet excited state ( 3 NPX*–His). Analysis of the NPX–His and NPX–Trp photolysates by UPLC-MS–MS revealed in both cases the formation of two photoproducts, arising from the reaction of singlet oxygen (1 O2) with the amino acid moiety. The most remarkable feature of NPX–Trp systems was a fast and stereoselective intramolecular fluorescence quenching, which prevented the efficient formation of 3 NPX*–Trp, thus explaining their lower reactivity towards photooxygenation. Finally, the NPX–Tyr systems were nearly unreactive and exhibited photophysical properties essentially coincident with those of the parent NPX. Overall, these results point to a type II photooxygenation mechanism, triggered by generation of 1 O2 from the 3 NPX* chromophoreFinancial support from the Spanish Government (CTQ2010-14882, JCI-2011-09926, Miguel Servet CP11/00154), from the EU (PCIG12-GA-2012-334257), from the Universitat Politecnica de Valencia (SP20120757) and from the Conselleria de Educacio, cultura i Esport (PROMETEOII/2013/005, GV/2013/051) is gratefully acknowledged.Vayá Pérez, I.; Andreu Ros, MI.; Jiménez Molero, MC.; Miranda Alonso, MÁ. (2014). Photooxygenation mechanisms in naproxen-amino acid linked systems. Photochemical & Photobiological Sciences Photochemical and Photobiological Sciences. 13:224-230. https://doi.org/10.1039/c3pp50252jS22423013L. I. Grossweiner and K. C.Smith, Photochemistry, in The Science of Photobiology, ed. K. C. Smith, Plenum Press, New York, 2nd edn, 1989, pp. 47–78L. Pretali and A.Albini, in CRC Handbook of Organic Photochemistry and Photobiology, ed. A. Griesbeck, M. Oelgemöller and F. Ghetti, CRC Press, Boca Raton, FL, 3rd edn, 2012, pp. 369–391Foote, C. S. (1991). DEFINITION OF TYPE I and TYPE II PHOTOSENSITIZED OXIDATION. Photochemistry and Photobiology, 54(5), 659-659. doi:10.1111/j.1751-1097.1991.tb02071.xDavies, M. J. (2003). Singlet oxygen-mediated damage to proteins and its consequences. Biochemical and Biophysical Research Communications, 305(3), 761-770. doi:10.1016/s0006-291x(03)00817-9Davies, M. J. (2004). Reactive species formed on proteins exposed to singlet oxygen. Photochemical & Photobiological Sciences, 3(1), 17. doi:10.1039/b307576cGirotti, A. W. (2001). Photosensitized oxidation of membrane lipids: reaction pathways, cytotoxic effects, and cytoprotective mechanisms. Journal of Photochemistry and Photobiology B: Biology, 63(1-3), 103-113. doi:10.1016/s1011-1344(01)00207-xAndreu, I., Morera, I. M., Boscá, F., Sanchez, L., Camps, P., & Miranda, M. A. (2008). Cholesterol–diaryl ketone stereoisomeric dyads as models for «clean» type I and type II photooxygenation mechanisms. Organic & Biomolecular Chemistry, 6(5), 860. doi:10.1039/b718068cStadtman, E. R. (1993). Oxidation of Free Amino Acids and Amino Acid Residues in Proteins by Radiolysis and by Metal-Catalyzed Reactions. Annual Review of Biochemistry, 62(1), 797-821. doi:10.1146/annurev.bi.62.070193.004053Garrison, W. M. (1987). Reaction mechanisms in the radiolysis of peptides, polypeptides, and proteins. Chemical Reviews, 87(2), 381-398. doi:10.1021/cr00078a006P. U. Giacomoni , Sun Protection in Man, Comprehensive Series in Photosciences, Elsevier, Amsterdam, 2001, vol. 3R. C. Straight and J. D.Spikes, Photosensitized oxidation of biomolecules. in Polymers and Biopolymers, ed. A. A. Frimer and O. Singlet, CRC Press, Boca Raton, FL, 1985, pp. 91–143Wright, A., Bubb, W. A., Hawkins, C. L., & Davies, M. J. (2002). Singlet Oxygen–mediated Protein Oxidation: Evidence for the Formation of Reactive Side Chain Peroxides on Tyrosine Residues¶. Photochemistry and Photobiology, 76(1), 35. doi:10.1562/0031-8655(2002)0762.0.co;2Agon, V. V., Bubb, W. A., Wright, A., Hawkins, C. L., & Davies, M. J. (2006). Sensitizer-mediated photooxidation of histidine residues: Evidence for the formation of reactive side-chain peroxides. Free Radical Biology and Medicine, 40(4), 698-710. doi:10.1016/j.freeradbiomed.2005.09.039Huyett, J. E., Doan, P. E., Gurbiel, R., Houseman, A. L. P., Sivaraja, M., Goodin, D. B., & Hoffman, B. M. (1995). Compound ES of Cytochrome c Peroxidase Contains a Trp .pi.-Cation Radical: Characterization by Continuous Wave and Pulsed Q-Band External Nuclear Double Resonance Spectroscopy. Journal of the American Chemical Society, 117(35), 9033-9041. doi:10.1021/ja00140a021Redmond, R. W., & Gamlin, J. N. (1999). A Compilation of Singlet Oxygen Yields from Biologically Relevant Molecules. Photochemistry and Photobiology, 70(4), 391-475. doi:10.1111/j.1751-1097.1999.tb08240.xA. J. Lewis and D. E.Furst, Nonsteroidal Anti-Inflammatory Drugs: Mechanisms and Clinical Uses, Marcel Dekker, New York, 2nd edn, 1994Boscá, F., Marín, M. L., & Miranda, M. A. (2001). Photoreactivity of the Nonsteroidal Anti-inflammatory 2-Arylpropionic Acids with Photosensitizing Side Effects¶. Photochemistry and Photobiology, 74(5), 637. doi:10.1562/0031-8655(2001)0742.0.co;2Beijersbergen van Henegouwen, G. M. J. (1991). New trends in photobiology. Journal of Photochemistry and Photobiology B: Biology, 10(3), 183-210. doi:10.1016/1011-1344(91)85002-xMiranda, M. A., Castell, J. V., Hernández, D., Gómez-Lechón, M. J., Bosca, F., Morera, I. M., & Sarabia, Z. (1998). Drug-Photosensitized Protein Modification:  Identification of the Reactive Sites and Elucidation of the Reaction Mechanisms with Tiaprofenic Acid/Albumin as Model System†. Chemical Research in Toxicology, 11(3), 172-177. doi:10.1021/tx970082dJiménez, M. C., Pischel, U., & Miranda, M. A. (2007). Photoinduced processes in naproxen-based chiral dyads. Journal of Photochemistry and Photobiology C: Photochemistry Reviews, 8(3), 128-142. doi:10.1016/j.jphotochemrev.2007.10.001Catalfo, A., Bracchitta, G., & De Guidi, G. (2009). Role of aromatic amino acid tryptophan UVA-photoproducts in the determination of drug photosensitization mechanism: a comparison between methylene blue and naproxen. Photochemical & Photobiological Sciences, 8(10), 1467. doi:10.1039/b9pp00028cVayá, I., Pérez-Ruiz, R., Lhiaubet-Vallet, V., Jiménez, M. C., & Miranda, M. A. (2010). Drug–protein interactions assessed by fluorescence measurements in the real complexes and in model dyads. Chemical Physics Letters, 486(4-6), 147-153. doi:10.1016/j.cplett.2009.12.091Vayá, I., Jiménez, M. C., & Miranda, M. A. (2007). Excited-State Interactions in Flurbiprofen−Tryptophan Dyads. The Journal of Physical Chemistry B, 111(31), 9363-9371. doi:10.1021/jp071301zVayá, I., Bonancía, P., Jiménez, M. C., Markovitsi, D., Gustavsson, T., & Miranda, M. A. (2013). Excited state interactions between flurbiprofen and tryptophan in drug–protein complexes and in model dyads. Fluorescence studies from the femtosecond to the nanosecond time domains. Physical Chemistry Chemical Physics, 15(13), 4727. doi:10.1039/c3cp43847cGriesbeck, A. G., Neudörfl, J., & de Kiff, A. (2011). Photoinduced electron-transfer chemistry of the bielectrophoric N-phthaloyl derivatives of the amino acids tyrosine, histidine and tryptophan. Beilstein Journal of Organic Chemistry, 7, 518-524. doi:10.3762/bjoc.7.60Giese, B., Wang, M., Gao, J., Stoltz, M., Müller, P., & Graber, M. (2009). Electron Relay Race in Peptides. The Journal of Organic Chemistry, 74(10), 3621-3625. doi:10.1021/jo900375fCordes, M., Köttgen, A., Jasper, C., Jacques, O., Boudebous, H., & Giese, B. (2008). Influence of Amino Acid Side Chains on Long-Distance Electron Transfer in Peptides: Electron Hopping via «Stepping Stones». Angewandte Chemie International Edition, 47(18), 3461-3463. doi:10.1002/anie.200705588Abraham, B., & Kelly, L. A. (2003). Photooxidation of Amino Acids and Proteins Mediated by Novel 1,8-Naphthalimide Derivatives. The Journal of Physical Chemistry B, 107(45), 12534-12541. doi:10.1021/jp0358275Cadenas, E. (1989). Biochemistry of Oxygen Toxicity. Annual Review of Biochemistry, 58(1), 79-110. doi:10.1146/annurev.bi.58.070189.000455Peña, D., Martí, C., Noneil, S., Martínez, L. A., & Miranda, M. A. (1997). Time-Resolved Near Infrared Studies on Singlet Oxygen Production by the Photosensitizing 2-Arylpropionic Acids. Photochemistry and Photobiology, 65(5), 828-832. doi:10.1111/j.1751-1097.1997.tb01930.xKerwin, B. A., & Remmele, R. L. (2007). Protect from Light: Photodegradation and Protein Biologics. Journal of Pharmaceutical Sciences, 96(6), 1468-1479. doi:10.1002/jps.20815Kang, P., & Foote, C. S. (2000). Synthesis of a 13C,15N labeled imidazole and characterization of the 2,5-endoperoxide and its decomposition. Tetrahedron Letters, 41(49), 9623-9626. doi:10.1016/s0040-4039(00)01731-7Saito, I., Matsuura, T., Nakagawa, M., & Hino, T. (1977). Peroxidic intermediates in photosensitized oxygenation of tryptophan derivatives. Accounts of Chemical Research, 10(9), 346-352. doi:10.1021/ar50117a00

Pennsylvania Folklife Vol. 12, No. 3

• Antiques in Dutchland • Antique or Folk Art: Which? • Pennsylvania Dutch • Amish Barn Raisings • Building a Pennsylvania Barn • Water Witching • Amish Family Life: A Sociologist\u27s Analysis • Straw Hat Making Among the Old Order Amish • Bread and Apple-Butter Day • Schnitz in the Pennsylvania Folk-Culture • Dutch Country Scarecrows • The Man Who Was Buried Standing Up • Living Occult Practices in Dutch Pennsylvania • Farewell to Olliehttps://digitalcommons.ursinus.edu/pafolklifemag/1011/thumbnail.jp

Coupling of kinesin ATP turnover to translocation and microtubule regulation: one engine, many machines

The cycle of ATP turnover is integral to the action of motor proteins. Here we discuss how variation in this cycle leads to variation of function observed amongst members of the kinesin superfamily of microtubule associated motor proteins. Variation in the ATP turnover cycle among superfamily members can tune the characteristic kinesin motor to one of the range of microtubule-based functions performed by kinesins. The speed at which ATP is hydrolysed affects the speed of translocation. The ratio of rate constants of ATP turnover in relation to association and dissociation from the microtubule influence the processivity of translocation. Variation in the rate-limiting step of the cycle can reverse the way in which the motor domain interacts with the microtubule producing non-motile kinesins. Because the ATP turnover cycle is not fully understood for the majority of kinesins, much work remains to show how the kinesin engine functions in such a wide variety of molecular machines

Safety and Performance of the Omnipod Hybrid Closed-Loop System in Adults, Adolescents, and Children with Type 1 Diabetes over 5 Days under Free-Living Conditions

Background: The objective of this study was to assess the safety and performance of the Omnipod\uae personalized model predictive control (MPC) algorithm in adults, adolescents, and children aged 656 years with type 1 diabetes (T1D) under free-living conditions using an investigational device. Materials and Methods: A 96-h hybrid closed-loop (HCL) study was conducted in a supervised hotel/rental home setting following a 7-day outpatient standard therapy (ST) phase. Eligible participants were aged 6-65 years with A1C <10.0% using insulin pump therapy or multiple daily injections. Meals during HCL were unrestricted, with boluses administered per usual routine. There was daily physical activity. The primary endpoints were percentage of time with sensor glucose <70 and 65250 mg/dL. Results: Participants were 11 adults, 10 adolescents, and 15 children aged (mean \ub1 standard deviation) 28.8 \ub1 7.9, 14.3 \ub1 1.3, and 9.9 \ub1 1.0 years, respectively. Percentage time 65250 mg/dL during HCL was 4.5% \ub1 4.2%, 3.5% \ub1 5.0%, and 8.6% \ub1 8.8% per respective age group, a 1.6-, 3.4-, and 2.0-fold reduction compared to ST (P = 0.1, P = 0.02, and P = 0.03). Percentage time <70 mg/dL during HCL was 1.9% \ub1 1.3%, 2.5% \ub1 2.0%, and 2.2% \ub1 1.9%, a statistically significant decrease in adults when compared to ST (P = 0.005, P = 0.3, and P = 0.3). Percentage time 70-180 mg/dL increased during HCL compared to ST, reaching significance for adolescents and children: HCL 73.7% \ub1 7.5% vs. ST 68.0% \ub1 15.6% for adults (P = 0.08), HCL 79.0% \ub1 12.6% vs. ST 60.6% \ub1 13.4% for adolescents (P = 0.01), and HCL 69.2% \ub1 13.5% vs. ST 54.9% \ub1 12.9% for children (P = 0.003). Conclusions: The Omnipod personalized MPC algorithm was safe and performed well over 5 days and 4 nights of use by a cohort of participants ranging from youth aged 656 years to adults with T1D under supervised free-living conditions with challenges, including daily physical activity and unrestricted meals