Ashley Arnold (winterdry8)

BACKGROUND Despite significant strides in understanding the pathophysiology of non-small cell lung cancer (NSCLC), these neoplasms typically present with intrinsic chemo- and radiotherapeutic resistance. Transcriptomic analyses of patient NSCLC tumors stratified by survival times have identified the PTEN-induced putative kinase 1 (PINK1 ) as a molecular governor of tumor aggressiveness and patient survival time. PINK1 has been shown to confer neuroprotection in models of Parkinson Disease by ensuring proper mitochondrial turnover (mitophagy), the upkeep of ATP production and sequestering of reactive oxygen species (ROS). METHODS We utilized an shRNA against PINK1 and the glycolytic inhibitor 3-BP to assess effects on NSCLC viability via MTS cell viability assay. DBZ inhibitor solubility dmso ATP levels, caspase-9 activation, mitophagy and ROS production were determined with standardly available kits. Cytochrome c cellular localization and phosphorylated parkin levels were determined using an ELISA. RESULTS Our results demonstrate that PINK1 depletion in the NSCLC cell line A549 via shRNA, reduced cancer cell proliferation, increased cell death, reduced ATP production, inhibited mitophagy and increased ROS and caspase-9-dependent apoptosis. PINK1 depleted cells were more susceptible to the glycolytic inhibitor 3-bromopyruvate (3-BP), which further perturbed ATP production. PINK1 depletion and 3-BP synergistically increased ROS production, caspase-9-dependent apoptosis and additively repressed mitophagy. CONCLUSIONS These results suggest that PINK1 depletion alters energetic metabolism and confers sensitivity to agents that inhibit glycolysis. Targeting accelerated tumor cell metabolism may prove useful in the clinical setting while sparing non-malignant tissue.BACKGROUND Increased mortality due to type 2 diabetes mellitus (T2DM) has been associated with renal and/or cardiovascular dysfunction. Dipeptidyl dipeptidase-4 inhibitors (iDPP-4s) may exert cardioprotective effects through their pleiotropic actions via glucagon-like peptide 1-dependent mechanisms. In this study, the pharmacological profile of a new iDPP-4 (LASSBio-2124) was investigated in rats with cardiac and renal dysfunction induced by T2DM. METHODS T2DM was induced in rats by 2 weeks of a high-fat diet followed by intravenous injection of streptozotocin. Metabolic disturbance and cardiac, vascular, and renal dysfunction were analyzed in the experimental groups. RESULTS Sitagliptin and LASSBio-2124 administration after T2DM induction reduced elevated glucose levels to 319.8 ±13.2 and 279.7 ± 17.8 mg/dL, respectively (p less then 0.05). LASSBio-2124 also lowered the cholesterol and triglyceride levels from 76.8 ±8.0 to 42.7 ± 3.2 mg/dL and from 229.7 ±25.4 to 100.7 ± 17.1 mg/dL, in diabetic rats. Sitagliptin and LASSBio-2124 reversed the reduction of the plasma insulin level. LASSBio-2124 recovered the increased urinary flow in diabetic animals and reduced 24-h proteinuria from 23.7 ±1.5 to 13.3 ±2.8 mg (p less then 0.05). It also reduced systolic and diastolic left-ventricular dysfunction in hearts from diabetic rats. CONCLUSION The effects of LASSBio-2124 were superior to those of sitagliptin in the cardiovascular systems of T2DM rats. This new prototype showed promise for the avoidance of comorbidities in a T2DM experimental model, and thus may constitute an innovative therapeutic agent for the treatment of these conditions in the clinical field in future.BACKGROUND The present study evaluated the antioxidant, antinociceptive and anti-edematogenic effects of Se-[(2,2-dimethyl-l,3-dioxolan-4-yl) methyl] 4-chlorobenzoselenolate (Se-DMC). METHODS In vitro experiments were carried out to evaluate Se-DMC antioxidant action. Thiobarbituric acid reactive species levels, 2,2'-diphenyl-l-picrylhydrazyl and 2,2'-azino-bis(3-thylbenzthiazoline-6-sulfonic acid) radicals scavenging and glutathione S-transferase-like activity were determined. Male Swiss mice were orally pre