The TSPO Ligands MGV-1 and 2-Cl-MGV-1 Differentially Inhibit the Cigarette Smoke-Induced Cytotoxicity to H1299 Lung Cancer Cells.

TSPO is involved in cigarette smoke (CS)-induced cellular toxicity, which may result in oral and pulmonary diseases and lung cancer. H1299 lung cancer cells were exposed directly to CS. The H1299 cells were pretreated with our TSPO ligands MGV-1 and 2-Cl-MGV-1 (Ki = 825 nM for both) at a concentration of 25 µM 24 h prior to CS exposure. Cell death and apoptotic markers were measured, in addition to TSPO expression levels, ATP synthase activity, generation of reactive oxygen species (ROS), depolarization of mitochondrial membrane potential (ΔΨm), cAMP and LDH levels. Pretreatment with MGV-1 and 2-Cl-MGV-1 (25 µM), 24 h prior to CS exposure, differentially attenuated the CS-induced cellular insult as well as cell death in H1299 lung cancer cells. These protective effects included prevention of ATP synthase reversal, ROS generation, depolarization of the mitochondrial membrane and elevation in LDH. The preventive efficacy of 2-Cl-MGV-1 was superior to that achieved by MGV-1. Both ligands did not prevent the elevation in cAMP. These findings may indicate a mild protective effect of these TSPO ligands in CS-related pulmonary and keratinocyte cellular pathology.

Liposomal Carrier Conjugated to APP-Derived Peptide for Brain Cancer Treatment.

Brain tumors are hard to treat with the currently available therapy. The major obstacle in the treatment of brain tumors is the lack of therapeutic strategies capable to penetrate the blood-brain barrier (BBB). The BBB is an endothelial interface that separates the brain from the circulatory blood system and prevents the exposure of the central nervous system (CNS) to circulating toxins and potentially harmful compounds. Unfortunately, the BBB prevents also the penetration of therapeutic compounds into the brain. We present here a drug-delivery liposomal carrier, conjugated to a peptide inserted in the liposomal membrane, which is putatively recognized by BBB transporters. The peptide is a short sequence of 5 amino acids (RERMS) present in the amyloid precursor protein (APP). This APP-targeted liposomal system was designed specifically for transporting compounds with anti-cancer activity via the BBB into the brain in an effective manner. This drug-delivery liposomal carrier loaded with the anti-cancer compounds temozolomide (TMZ), curcumin, and doxorubicin crossed the BBB in an in vitro model as well as in vivo (mice model). In the in vitro model, the targeted liposomes crossed the BBB model fourfold higher than the non-targeted liposomes. Labeled targeted liposomes penetrated the brain in vivo 35% more than non-targeted liposomes. Treatment of mice that underwent intracranial injection of human U87 glioblastoma, with the targeted liposomes loaded with the three tested anti-cancer agents, delayed the tumor growth and prolonged the mice survival in a range of 45% -70%. It appears that the targeted liposomal drug-delivery system enables better therapeutic efficacy in a SCID mouse model of glioblastoma compared to the corresponding non-targeted liposomes and the free compounds.

Effect of Vitamin D Level on Clinical Outcomes in Patients Undergoing Left Ventricular Assist Device Implantation.

BACKGROUND: Vitamin D is an important hormone that regulates cardiac myocyte function. Low levels contribute to the development of cardiovascular disease and have been implicated in immune function and the inflammatory cascade. Patients who undergo left ventricular assist device (LVAD) implantation are at risk for driveline infection, stroke, and gastrointestinal (GI) bleeding. We investigated whether serum 25-hydroxy (25-OH) vitamin D levels affect clinical outcomes after LVAD. METHODS: 212 patients who underwent LVAD implantation between 2010 and 2015 were included. We measured preoperative 25-OH vitamin D level and postoperative adverse events during the first year. Vitamin D level was classified into 3 categories: normal (>30 ng/mL), insufficient (20-30 ng/mL), and deficient (<20 ng/mL). Clinical outcomes in both insufficient and deficient categories were compared with the normal category. RESULTS: The odds ratio (OR) of being admitted ≥2 times was 2.46 (95% confidence interval [CI]: 1.067-5.769) for deficiency and 2.5 (95% CI: 0.970-6.443) for insufficiency. The OR of driveline infection was 6.185 (95% CI: 0.80-49.2; P = .07) for insufficiency and 11.467 (95% CI: 1.204-109.26; P = .03) for deficiency. Vitamin D levels were not associated with GI bleeding, length of stay, or stroke. CONCLUSIONS: In patients with LVAD, both deficiency and insufficiency of 25-OH vitamin D levels are independently associated with increased postoperative driveline infection risk and higher rate of readmission. Further trials are needed to confirm whether a repletion regimen could be a promising means of decreasing the risk for these postoperative adverse events.