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Tobacco smoke is a complex mixture of more than 7000 chemicals, of which many are toxic and/or carcinogenic. Many hazard assessments of tobacco have focused on individual chemical exposures without consideration of how the chemicals may interact with one another. Two chemicals, the human carcinogen 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) and a possible human carcinogen, acrolein, were hypothesized to interact with one another, possibly owing to the additive effects of DNA adduct formation or influence on the repair of mutagenic DNA adducts. To test our hypothesis that coexposure to NNK and acrolein is more carcinogenic than either chemical alone, A/J mice were exposed to NNK (i.p., 0, 2.5, or 7.5 μmol in saline) in the presence or absence of inhaled acrolein (15 ppmV). While the single 3 h exposure to acrolein alone did not induce lung adenomas, it significantly enhanced NNK's lung carcinogenicity. In addition, mice receiving both NNK and acrolein had more adenomas with dysplasia or progression than those receiving only NNK, suggesting that acrolein may also increase the severity of NNK-induced lung adenomas. To test the hypothesis that the interaction was due to effects on DNA adduct formation and repair, NNK- and acrolein pulmonary DNA adduct levels were assessed. There was no consistent effect of the coexposure on NNK-derived DNA adducts, and acrolein DNA adducts were not elevated above endogenous levels. This study supports the hypothesis that tobacco smoke chemicals combine to contribute to the carcinogenic potency of tobacco smoke, and the mechanism of interaction cannot be explained by alterations of DNA adduct levels.

More than 20% of the US population suffers from laryngopharyngeal reflux. Although dietary/lifestyle modifications and alginates provide benefit to some, there is no gold standard medical therapy. Increasing evidence suggests that pepsin is partly, if not wholly, responsible for damage and inflammation caused by laryngopharyngeal reflux. A treatment specifically targeting pepsin would be amenable to local, inhaled delivery, and could prove effective for endoscopic signs and symptoms associated with nonacid reflux. The aim herein was to identify small molecule inhibitors of pepsin and test their efficacy to prevent pepsin-mediated laryngeal damage in vivo.Drug and pepsin binding and inhibition were screened by high-throughput assays and crystallography. A mouse model of laryngopharyngeal reflux (mechanical laryngeal injury once weekly for 2 weeks and pH 7 solvent/pepsin instillation 3 days/week for 4 weeks) was provided inhibitor by gavage or aerosol (fosamprenavir or darunavir; 5 days/week for 4 weeks; n = 3). Larynges were collected for histopathologic analysis.HIV protease inhibitors amprenavir, ritonavir, saquinavir, and darunavir bound and inhibited pepsin with ICFosamprenavir and darunavir, FDA-approved therapies for HIV/AIDS, bind and inhibit pepsin, abrogating pepsin-mediated laryngeal damage in a laryngopharyngeal reflux mouse model. These drugs target a foreign virus, making them ideal to repurpose. Reformulation for local inhaled delivery could further improve outcomes and limit side effects.NA. Laryngoscope, 2022.

The compositionally distinct lipid rafts present in the plasma membrane regulate the restrictive trafficking and signal transduction in the blood-brain barrier (BBB) endothelium. Several metabolic and neurodegenerative diseases are associated with lipid homeostasis disruption within the BBB endothelium. Here, we hypothesized that the delivery of lipid triglyceride based nanoemulsions containing unsaturated fatty acids (UFAs) provides a novel non-pharmacological approach to modulate lipid raft integrity and rectify the aberrant trafficking and signal transduction. The current study has shown that soybean oil nanoemulsions (SNEs) altered the morphology of lipid rafts that are stained by Alex Fluor 647 labelled cholera toxin (AF647-CTX) in polarized human cerebral microvascular endothelial (hCMEC/D3) cell monolayers. Moreover, western blot and flow cytometry analysis showed that SNEs containing polyunsaturated fatty acids (PUFAs) increased phospo-AKT (p-AKT) expression, a marker for the stimulation of metabolic arm of insulin signaling, and insulin uptake in hCMEC/D3 monolayers. However, olive oil nanoemulsions (ONEs) containing monounsaturated fatty acids (MUFAs) had no detectable impact on lipid raft integrity, AKT phosphorylation, or insulin uptake. These findings provided direct evidence that SNEs containing PUFAs can upregulate insulin-pAKT pathway, facilitate insulin trafficking at the BBB, and potentially address cerebrovascular dysfunction in metabolic and neurodegenerative diseases.