Revision of the Crystal structure of the orthorhombic polymorph of oxyma: on the importance of π-hole interactions and their interplay with H-bonds

In this work the crystal structure of the previously described orthorhombic polymorph of the coupling reagent Oxyma has been revised, corrected now as centrosymmetric and analyzed by means of DFT calculations. In the solid state the structure forms a network of H-bonds and self-assembled dimers that are held together by the formation of N···C π-hole interactions involving the C-atom of the imino group. The H-bonding and π-hole interactions observed in the solid state were rationalized using molecular electrostatic potential (MEP) surfaces, focusing on the H-bond donor-acceptor groups and the π-hole observed above and below the molecular plane. The interactions and their interplay have been characterized by using two methodologies based on the topology of the electron density, which are the quantum theory of 'atom-in-molecules' (QTAIM) and the noncovalent interaction plot (NCIplot)

Crystal engineering of nutraceutical phytosterols: new cocrystal solid solutions?

A cocrystal screening conducted with solid solutions of three phytosterols (β-sitosterol, campesterol and stigmasterol) and a set of coformers with strong hydrogen bond donors reveals that multicomponent solid solutions are preferentially formed instead of pure cocrystals and are much enriched with β-sitosterol with respect to stigmasterol, a natural product with cytotoxicity concerns

Gallic Acid Dimer As a Double π−Hole Donor: Evidence from X‑ray, Theoretical Calculations, and Generalization from the Cambridge Structural Database

In this work, we demonstrate that the centrosymmetric eight-membered supramolecular ring R2 2 (8) that is formed upon dimerization of benzoic acids has a marked tendency to establish π−hole interactions with electron-rich atoms. We have used the Cambridge Structural Database to demonstrate the preference of carboxylic acid dimers to form donor−acceptor interactions involving π−holes located at the C atoms above and below the molecular plane. Moreover, we have carried out DFT calculations (PBE0-D3/def2-TZVP) to investigate the geometric and energetic features of these interactions and how they are affected by the substituents of the aromatic ring. Finally, as an example we report the synthesis and X-ray characterization of a solvate of gallic acid with dioxane, where two molecules of dioxane are located above and below the eight-membered supramolecular ring, forming two symmetrically equivalent O···C π−hole interactions

A Novel, Extremely Bioavailable Cocrystal of Pterostilbene

New multicomponent solid forms of the nutraceutical pterostilbene have been discovered and characterized through experimental cocrystal screening. Among the coformers tested, picolinic acid formed a cocrystal with a 10-fold enhancement of oral bioavailability in rats, which converts the new cocrystal into a very promising candidate for new formulations of pterostilbene with improved performance

Ischemic Tolerance Protects the Rat Retina from Glaucomatous Damage

Glaucoma is a leading cause of acquired blindness which may involve an ischemic-like insult to retinal ganglion cells and optic nerve head. We investigated the effect of a weekly application of brief ischemia pulses (ischemic conditioning) on the rat retinal damage induced by experimental glaucoma. Glaucoma was induced by weekly injections of chondroitin sulfate (CS) in the rat eye anterior chamber. Retinal ischemia was induced by increasing intraocular pressure to 120 mmHg for 5 min; this maneuver started after 6 weekly injections of vehicle or CS and was weekly repeated in one eye, while the contralateral eye was submitted to a sham procedure. Glaucoma was evaluated in terms of: i) intraocular pressure (IOP), ii) retinal function (electroretinogram (ERG)), iii) visual pathway function (visual evoked potentials, (VEPs)) iv) histology of the retina and optic nerve head. Retinal thiobarbituric acid substances levels were assessed as an index of lipid peroxidation. Ischemic conditioning significantly preserved ERG, VEPs, as well as retinal and optic nerve head structure from glaucomatous damage, without changes in IOP. Moreover, ischemia pulses abrogated the increase in lipid peroxidation induced by experimental glaucoma. These results indicate that induction of ischemic tolerance could constitute a fertile avenue for the development of new therapeutic strategies in glaucoma treatment

Circadian variations of prostaglandin E2 and F2 α release in the golden hamster retina

Circadian variations of prostaglandin E2 and F2α release were examined in the golden hamster retina. Both parameters showed significant diurnal variations with maximal values at midnight. When hamsters were placed under constant darkness for 48 h, the differences in prostaglandin release between subjective mid-day and subjective midnight persisted. Western blot analysis showed that cyclooxygenase (COX)-1 levels were significantly higher at midnight than at mid-day, and at subjective midnight than at subjective mid-day, whereas no changes in COX-2 levels were observed among these time points. Immunohistochemical studies indicated the presence of COX-1 and COX-2 in the inner (but not outer) retina. Circadian variations of retinal prostaglandin release were also assessed in suprachiasmatic nuclei (SCN)-lesioned animals. Significant differences in retinal prostaglandin release between subjective mid-day and subjective midnight were observed in SCN-lesioned animals. These results indicate that hamster retinal prostaglandin release is regulated by a retinal circadian clock independent from the SCN. Thus, the present results suggest that the prostaglandin/COX-1 system could be a retinal clock output or part of the retinal clock mechanism.Fil: de Zavalía, Nuria María Asunción. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Fernández, Diego Carlos. Universidad de Morón. Facultad de Medicina; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Sande Casal, Pablo Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; ArgentinaFil: Keller Sarmiento, María Inés. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Golombek, Diego Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; ArgentinaFil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; ArgentinaFil: Silberman, Dafne Magalí. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentin

ONH sections from a control or a CS-treated eye without or with ischemia pulses.

<p>(A) Healthy, intact control optic nerve. Note the homogeneity of the staining. In vehicle-injected eyes, individual axons were generally uniform in shape, rounded and packed together tightly to form the fibers of the healthy nerve. In CS-treated eye without ischemia pulses (B) a less stained area indicates a nerve alteration. Disease in individual axons was characterized by axonal distention and distortion that resulted in a departure from the circular morphology of normal axons. In contrast, a conserved structure of the ONH was observed in the CS-treated eye with ischemia pulses (C). Toluidine blue. (D) Number of axons in eyes injected with vehicle or CS without or with ischemia pulses. A significant decrease in the axon number was observed in CS- injected eyes without ischemia pulses as compared with vehicle-injected eyes (sham), whereas ischemia pulses significantly preserved this parameter. Scale bar: 10 µm. Data are mean ± SEM (n = 5 eyes/group) *p<0.05 vehicle injected eyes without ischemia pulses (sham), a: p<0.05 versus CS-injected eyes without ischemia pulses (sham), by Tukey's test.</p

Retinal histology examination after 10 weeks of ocular hypertension.

<p>Upper panel: Representative photomicrographs of retinal sections stained with hematoxylin and eosin from a vehicle-injected eye, and a hypertensive eye without or with pulses of ischemia. Note the diminution of GCL cells in the eye injected with CS without ischemia pulses. The application of ischemia pulses preserved this parameter. The other retinal layers showed a normal appearance in all groups. Middle panel: Immunohistochemical detection of NeuN-positive neurons in the GCL from a vehicle-injected eye, a hypertensive eye without or with ischemia pulses. A strong NeuN-immunostaining (red) was confined to ganglion cells in the GCL. The number of NeuN positive ganglion cells was lower in hypertensive eyes without ischemia pulses than in vehicle- injected eyes, whereas the application of ischemia pulses in CS-injected eyes increased NeuN-immunostaining. A similar profile was observed for cell nuclei counterstained with DAPI (blue). Lower Panel: cell count in the GCL evaluated by H&E staining, NeuN immunostaining, and DAPI labeling. By all these methods, a significant decrease of the number of cells in the GCL was observed in CS- injected eyes without ischemia pulses as compared with vehicle-injected eyes (sham), whereas ischemia pulses significantly preserved this parameter in CS-injected eyes. Scale bar: Upper panel  =  50 µm; Middle panel  =  50 µm. Data are the mean ± SEM (n = 5 animals per group). * p<0.05, ** p<0.01 vehicle injected eyes without ischemia pulses (sham), a: p<0.05, b: p<0.01 versus CS-injected eyes without ischemia pulses (sham), by Tukey's test. GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer.</p

Effect of ischemia pulses on IOP in vehicle and CS-injected eyes.

<p>TonoPen measurements of IOP from eyes bilaterally injected with vehicle or CS and submitted to ischemia pulses or sham procedure. IOP was assessed at 6, 7, 8, 9, and 10 weeks of weekly intracameral injections. At all time points examined, CS significantly increased IOP as compared with vehicle-injected eyes. Ischemia pulses did not modify this parameter in vehicle or CS-injected eyes at any time point. Data are the mean ± SEM (n = 10 animals per group).</p><p>**p<0.01 versus vehicle-injected eyes without ischemia pulses (sham), by Tukey's test.</p