Vasoactivity of Rucaparib, a PARP-1 Inhibitor, is a Complex Process that Involves Myosin Light Chain Kinase, P2 Receptors, and PARP Itself

Therapeutic inhibition of poly(ADP-ribose) polymerase (PARP), as monotherapy or to supplement the potencies of other agents, is a promising strategy in cancer treatment. We previously reported that the first PARP inhibitor to enter clinical trial, rucaparib (AG014699), induced vasodilation in vivo in xenografts, potentiating response to temozolomide. We now report that rucaparib inhibits the activity of the muscle contraction mediator myosin light chain kinase (MLCK) 10-fold more potently than its commercially available inhibitor ML-9. Moreover, rucaparib produces additive relaxation above the maximal degree achievable with ML-9, suggesting that MLCK inhibition is not solely responsible for dilation. Inhibition of nitric oxide synthesis using L-NMMA also failed to impact rucaparib's activity. Rucaparib contains the nicotinamide pharmacophore, suggesting it may inhibit other NAD+-dependent processes. NAD+ exerts P2 purinergic receptor-dependent inhibition of smooth muscle contraction. Indiscriminate blockade of the P2 purinergic receptors with suramin abrogated rucaparib-induced vasodilation in rat arterial tissue without affecting ML-9-evoked dilation, although the specific receptor subtypes responsible have not been unequivocally identified. Furthermore, dorsal window chamber and real time tumor vessel perfusion analyses in PARP-1-/- mice indicate a potential role for PARP in dilation of tumor-recruited vessels. Finally, rucaparib provoked relaxation in 70% of patient-derived tumor-associated vessels. These data provide tantalising evidence of the complexity of the mechanism underlying rucaparib-mediated vasodilation.

Photosensitized destruction of Chlorella vulgaris by methylene blue or nuclear fast red combined with hydrogen peroxide under visible light irradiation

A considerable number of investigations have started to elucidate the essential roles biological agents play in the biodeterioration of stone. Chemical biocides are becoming increasingly banned because of the environmental and health hazards associated with these toxic substances. The present study reports the photodynamic effect of Methylene Blue (MB) and Nuclear Fast Red (NFR) in the presence of hydrogen peroxide (H₂O₂) on the destruction of the algae Chlorella vulgaris (C. vulgaris) under irradiation with visible light. Illumination of C. vulgaris in the presence of MB or NFR combined with H₂O₂ results in the decomposition of both the algal species and the photosensitizer. The photodynamic effect was investigated under aerobic and anaerobic conditions. Differences in mechanism type are reported and are dependent on both the presence and the absence of oxygen. The behavior of each photosensitizer leads to a Type II mechanism and a Type I/Type II combination for MB and NFR, respectively, being concluded. This novel combination could be effective for the remediation of biofilm-colonized stone surfaces.

Generalized collisional radiative model for light elements: C: Data for the B isonuclear sequence

A first stage collision database is assembled which contains electron-impact excitation, ionization,\r and recombination rate coefficients for B, B + , B 2+ , B 3+ , and B 4+ . The first stage database\r is constructed using the R-matrix with pseudostates, time-dependent close-coupling, and perturbative\r distorted-wave methods. A second stage collision database is then assembled which contains\r generalized collisional-radiative ionization, recombination, and power loss rate coefficients as a\r function of both temperature and density. The second stage database is constructed by solution of\r the collisional-radiative equations in the quasi-static equilibrium approximation using the first\r stage database. Both collision database stages reside in electronic form at the IAEA Labeled Atomic\r Data Interface (ALADDIN) database and the Atomic Data Analysis Structure (ADAS) open database.

Generalized collisional radiative model for light elements. Part B: Data for the Be isonuclear sequence

A first-stage collision database is assembled which contains electron-impact excitation, ionization, and recombination rate coefficients for Be, Be+, Be2+, and Be3+. The first-stage database is constructed using the R-matrix with pseudo-states, time-dependent close-coupling, and perturbative, distorted-wave methods. A second-stage collision database is then assembled which contains generalized collisional-radiative and radiated power loss coefficients. The second-stage database is constructed by solution of collisional-radiative equations in the quasi-static equilibrium approximation using the first-stage database. Both collision database stages reside in electronic form at the ORNL Controlled Fusion Atomic Data Center and in the ADAS database, and are easily accessed over the worldwide internet. © 2007 Elsevier Inc. All rights reserved.

Generalised collisional-radiative model for light elements. A: Data for the Li isonuclear sequence

A first stage collision database is assembled which contains electron-impact effective collision strengths, and ionization and recombination rate coefficients for Li, Li+, and Li2+. The first stage database is constructed using the R-matrix with pseudo-states, time-dependent close-coupling, converged close-coupling, and perturbative distorted-wave methods. A second stage collision database is then assembled which contains generalized collisional-radiative and radiated power loss coefficients. The second stage database is constructed by solution of collisional-radiative equations in the quasi-static equilibrium approximation using the first stage database. Both collision database stages reside in electronic form at the ORNL Controlled Fusion Atomic Data Center and in the ADAS database, and are easily accessed over the worldwide internet. ?? 2006 Elsevier Inc. All rights reserved.