Nano encapsulated novel compound SA-10 with therapeutic activity in both acute and chronic murine hindlimb ischemia models.

The production dysregulation of reactive oxygen species (ROS) and nitric oxide (NO) in ischemic tissues results in endothelial dysfunction, hyperinflammation and poor blood circulation. Here, we report a hybrid molecule, SA-10 with both NO donating and ROS scavenging abilities that demonstrated potent cytoprotection and tube formation activity in endothelial cells under H2O2-induced oxidative stress. SA-10 loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (SA-10 NPs) were delivered intramuscularly (IM) to two murine hindlimb ischemia models. In the acute mode ischemia/reperfusion (I/R), the muscle damage, hyperinflammation, and lung edema were significantly reduced 3 days post-dose while in the chronic ischemia model, significant improvement of blood perfusion and physical endurance was observed over 30 days (P < 0.05). Elderly patients with acute and chronic limb ischemia have limited options for surgical or endovascular interventions, so we anticipate that a product like SA-10 NPs has potential as one of the therapeutic alternatives to surgery.

Novel Thiol Containing Hybrid Antioxidant-Nitric Oxide Donor Small Molecules for Treatment of Glaucoma.

Oxidative stress induced death and dysregulation of trabecular meshwork (TM) cells contribute to the increased intraocular pressure (IOP) in primary open angle (POAG) glaucoma patients. POAG is one of the major causes of irreversible vision loss worldwide. Nitric oxide (NO), a small gas molecule, has demonstrated IOP lowering activity in glaucoma by increasing aqueous humor outflow and relaxing TM. Glaucomatous pathology is associated with decreased antioxidant enzyme levels in ocular tissues causing increased reactive oxygen species (ROS) production that reduce the bioavailability of NO. Here, we designed, synthesized, and conducted in vitro studies of novel second-generation sulfur containing hybrid NO donor-antioxidants SA-9 and its active metabolite SA-10 to scavenge broad-spectrum ROS as well as provide efficient protection from t-butyl hydrogen peroxide (TBHP) induced oxidative stress while maintaining NO bioavailability in TM cells. To allow a better drug delivery, a slow release nanosuspension SA-9 nanoparticles (SA-9 NPs) was prepared, characterized, and tested in dexamethasone induced ocular hypertensive (OHT) mice model for IOP lowering activity. A single topical eye drop of SA-9 NPs significantly lowered IOP (61%) at 3 h post-dose, with the effect lasting up to 72 h. This class of molecule has high potential to be useful for treatment of glaucoma.

Investigation of gas phase absorption spectral similarity for stable-isotopically labeled compounds in the 125-240nm wavelength range.

Stable-isotopically-labeled internal standards are commonly incorporated in methods for trace analysis that utilize mass spectrometric detection. They closely mimic the physicochemical properties of the analyte, but their signal is easily differentiable based on a change in molecular mass. To investigate the potential to transfer methods incorporating such internal standards for analysis by vacuum ultraviolet detection, a study was conducted to compare the spectral shape (from 125 to 240nm) of stable-isotopically-labeled compounds with their non-labeled counterparts. Gas chromatography - vacuum ultraviolet spectroscopic analysis was performed for a series of benzene isotopologues, as well as for clinically- and environmentally-relevant standard compounds and their deuterated counterparts. The absorption characteristics of the benzene isotopologues were evaluated based on similarity (normalized spectra), as well as on their magnitude of absorption. In general, very minor differences in absorption spectra were observed; however, increasing degree of deuteration did generally increase the spectral difference between labeled and non-labeled analytes. Sum of squared residuals were used as quantitative measures to assess spectral similarity (and dissimilarity). Theoretical computation of absorption spectra for benzene using time-dependent density functional theory was also examined; though, further work is needed in this area to extend the analysis to isotopologue analysis.