COMPOSITIONS AND COMPOUNDS FOR USE AS MOLECULAR ADJUVANT FOR A NCOTINE WACCNE

Compounds are disclosed comprising molecular adjuvants having an antigen presenting cell-targeting ligand linked to a nicotine hapten. Methods are disclosed for employing the compounds as a nicotine vaccine for treatment or prevention of nicotine addiction

In vitro comparison of Ethanol Metabolism in Precision Cut Liver Slices from C57Bl/6, Balb/c, DBA/2J and 129S1/SvlmJ Mice and with the Aldeyra Product ADX-629

Alcoholic liver disease (ALD) is common consequence of excessive alcohol consumption [1]. When the liver is damaged by the intake of alcohol, repair mechanisms are deployed, which results in fibrosis or scarring of the liver. Development of this disease is due to the byproducts of ethanol metabolism. These byproducts include acetaldehyde from the metabolism of ethanol and malondialdehyde from the breakdown of cell membranes during injury. An Aldeyra product, ADX-629, is a small molecule that acts as a reactive aldehyde species (RASP) inhibitor. ADX-629 covalently binds free aldehydes, thus diminishing excessive RASP levels. To determine the aldehyde scavenging abilities of ADX-629 in attenuating fatty liver disease, precision cut liver slices (PCLS) were exposed to varying concentrations of ADX-629 as well as 25mM of ethanol. PCLS, which provide a novel in vitro/ex vivo experimental model, were then measured for triglyceride levels and supernatants were analyzed for acetaldehyde levels. It was found that ADX-629 reduced the acetaldehyde levels released from PCLS while also decreasing triglyceride levels. ADX-629 offers promising clinical uses such as in the prevention of fatty liver formation in patients with non-alcoholic steatohepatitis and in the treatment of alcoholic patients by preventing oxidative stress caused by the breakdown of ethanol thereby, preventing ALD.https://digitalcommons.unmc.edu/surp2021/1062/thumbnail.jp

Induction of autophagy markers is associated with attenuation of miR-133a in diabetic heart failure patients undergoing mechanical unloading.

Autophagy is ubiquitous in all forms of heart failure and cardioprotective miR-133a is attenuated in human heart failure. Previous reports from heart failure patients undergoing left ventricular assist device (LVAD) implantation demonstrated that autophagy is upregulated in the LV of the failing human heart. Studies in the murine model show that diabetes downregulates miR-133a. However, the role of miR-133a in the regulation of autophagy in diabetic hearts is unclear. We tested the hypothesis that diabetes exacerbates cardiac autophagy by inhibiting miR-133a in heart failure patients undergoing LVAD implantation. The miRNA assay was performed on the LV of 15 diabetic (D) and 6 non-diabetic (ND) heart failure patients undergoing LVAD implantation. Four ND with highly upregulated and 5 D with highly downregulated miR-133a were analyzed for autophagy markers (Beclin1, LC3B, ATG3) and their upstream regulators (mTOR and AMPK), and hypertrophy marker (beta-myosin heavy chain) by RT-qPCR, Western blotting and immunofluorescence. Our results demonstrate that attenuation of miR-133a in diabetic hearts is associated with the induction of autophagy and hypertrophy, and suppression of mTOR without appreciable difference in AMPK activity. In conclusion, attenuation of miR-133a contributes to the exacerbation of diabetes mediated cardiac autophagy and hypertrophy in heart failure patients undergoing LVAD implantation

Malondialdehyde Acetaldehyde Adducts (MAA-Adducts) Direct Distinctive Pro-Inflammatory Responses in Endothelial and Macrophage Cell Lines

Chronic inflammation plays a critical role in the pathogenesis of atherosclerosis. At present, the mechanism(s) by which inflammation contributes to this disease isnot entirely understood. Inflammation is known to induce oxidative stress, of which one consequence is lipid peroxidation. This process leads to the production of malondialdehyde (MDA), which can subsequently break down to form acetaldehyde (AA). These two aldehyde by-products can covalently interact with the ε-amino group of lysineswithin proteins and lipoproteins leading to the formation of highly immunogenic malondialdehyde-acetaldehyde adducts (MAA-adducts). The aim of this study was to determine the in-vitro cytokine response of endothelial cells and macrophages treated with MAA-modified human serum albumin (HSA-MAA) and low-density lipoprotein (LDL-MAA). In addition, cells isolated from mice with exposure to MAA and high fat diets were stained and imaged for uptake of the modified macromolecules of interest. We found that exposure of endothelial cells resulted in increased expression of IL-6, TNF-α, ICAM-1, VCAM-1, and MCP-1 in response to incubation with HSA-MAA; whereas, the same treatment of macrophages resulted in increased expression of IL-6, TNF-α, and IL-1b. LDL-MAA incubationresulted in increased TNF-α expression in macrophages, but MCP-1 was elevated in endothelial cells. Interestingly, the quantitative and qualitative uptake of triglycerides was increased in both endothelial and macrophage cells when exposed to LDL-MAA compared to LDL alone. The results of these studies demonstrate that different MAA-adducts elicit unique responses in different cell types. Additionally, the presence of MAA appears to modulate the cells leading to increased uptake of triglycerides and further progression of the inflammatory response.https://digitalcommons.unmc.edu/emet_posters/1003/thumbnail.jp