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. 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 pretreated with Se-DMC (1,10 and 50 mg/kg), meloxicam (50 mg/kg) or vehicle 30 min prior to acetic acid or glutamate test. To extend our knowledge of the pharmacological properties of this compound, it was tested in an inflammatory model through ear edema induced by croton oil. The contribution of glutamatergic and serotonergic systems was also investigated. RESULTS In vitro experiments revealed that Se-DMC exerts antioxidant activity. CC-92480 Nociception induced by glutamate or acetic acid was reduced by Se-DMC or meloxicam. Se-DMC diminished the paw edema formation induced by glutamate, while meloxicam did not show any effect. Se-DMC and meloxicam decreased the ear edema formation and protected against the increase in myeloperoxidase activity in mice ear induced by croton oil. The pretreatment of animals with MK-801 did not alter antinociception caused by Se-DMC in the glutamate test. The antinociceptive effect exerted by Se-DMC in the acetic acid test was reverted by the pretreatment of mice with different serotonergic antagonists (WAY100635, ketanserin and pindolol). CONCLUSIONS Data presented here showed that the modulation of serotonergic and glutamatergic systems and the anti-inflammatory and antioxidant actions could contribute to the antinociceptive and anti-edematogenic effects of Se-DMC and it supported the therapeutic potential of this compound.BACKGROUND Our previous study has demonstrated that activation of the 5-HT2, but not 5-HT1 serotonin receptor type in the hypothalamic arcuate nucleus (ARC) is responsible for the neuroendocrine regulation of liver cytochrome P450. The goal of these studies was to determine whether 5-HT2C serotonin receptor subtype in the ARC is engaged in the regulation of liver cytochrome P450. METHODS The 5-HT2C serotonin receptor agonist CP-809,101 was injected into the ARC for 5 days. The liver cytochrome P450 activity and protein level were measured. RESULTS In rats receiving an injection of the 5-HT2C serotonin receptor agonist CP-809,101 into the ARC (1 μg/side) for five days, the activities of CYP2B, CYP2C11 and CYP3A significantly increased corresponding with the elevated enzyme protein level. CONCLUSIONS The obtained results suggest that the 5-HT2C serotonin receptor subtype in the ARC is involved in the positive neuroendocrine regulation of cytochrome P450. Further studies are in progress to explain the physiological mechanism which is responsible for the observed regulation of cytochrome P450 by 5-HT2C receptor present in the ARC.