Pomegranate shows neuroprotective effects against Alzheimer's disease (AD) in several reported animal studies. However, whether its constituent ellagitannins and/or their physiologically relevant gut microbiota-derived metabolites, namely, urolithins (6H-dibenzo[b,d]pyran-6-one derivatives), are the responsible bioactive constituents is unknown. Therefore, from a pomegranate extract (PE), previously reported by our group to have anti-AD effects in vivo, 21 constituents, which were primarily ellagitannins, were isolated and identified (by HPLC, NMR, and HRESIMS). In silico computational studies, used to predict blood-brain barrier permeability, revealed that none of the PE constituents, but the urolithins, fulfilled criteria required for penetration. Urolithins prevented β-amyloid fibrillation in vitro and methyl-urolithin B (3-methoxy-6H-dibenzo[b,d]pyran-6-one), but not PE or its predominant ellagitannins, had a protective effect in Caenorhabditis elegans post induction of amyloid β(1-42) induced neurotoxicity and paralysis. Therefore, urolithins are the possible brain absorbable compounds which contribute to pomegranate's anti-AD effects warranting further in vivo studies on these compounds.

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34Although vital to the immune system, macrophages can act as reservoirs for 35 pathogens such as tuberculosis and human immunodeficiency virus. Limitations in the 36 treatment of such diseases include targeting therapeutics directly to macrophages and the 37 large systemic dosages needed. The objective of this study is to develop a nanoparticle 38 (NP)-based drug delivery system that can provide targeted delivery into macrophages. 39Acetalated dextran (Ac-Dex) NP loaded with the lipophilic model compound curcumin 40 (CUR) were synthesized and coated in 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine 41 (DPPS), a phospholipid that induces phagocytosis in macrophages. DPPS-CUR NP were 42 found to release 67.8% of encapsulated CUR within 24 hours at pH 5.35 and exhibited 43 minimal CUR release (6.3%) at pH 7.4. DPPS-CUR NP were uptaken by murine 44 macrophages significantly more than NP without DPPS coating and NP exposure to these 45 macrophages resulted in minimal toxicity to the cells and minimal nitric oxide production. 46These results suggest that the combination of the DPPS coating and pH-sensitive polymer 47Ac-Dex can provide a NP delivery system capable of enhanced uptake by macrophages 48 and potential systemic stability to more effectively deliver drugs of interest. As a result, 49 the described DPPS-CUR NP can serve as a viable delivery system for the treatment of 50 macrophage-associated diseases.

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