Extracellular vesicles (EVs) are a highly heterogeneous population of membranous particles that are secreted by almost all types of cells across different domains of life, including plants. In recent years, studies on plant-derived nanovesicles (PDNVs) showed that they could modulate metabolic reactions of the recipient cells, affecting (patho)physiology with health benefits in a trans-kingdom manner. In addition to its bioactivity, PDNV has advantages over conventional nanocarriers, making its application promising for therapeutics delivery. Here, we discuss the characteristics of PDNV and highlight up-to-date pre-clinical and clinical evidence, focusing on therapeutic application.

Obesity caused by overnutrition is a major risk factor for non-alcoholic fatty liver disease (NAFLD). Several lipid intermediates such as fatty acids, glycerophospholipids and sphingolipids are implicated in NAFLD, but detailed characterization of lipids and their functional links to proteome and phosphoproteome remain to be elucidated. To characterize this complex molecular relationship, we used a multi-omics approach by conducting comparative proteomic, phoshoproteomic and lipidomic analyses of high fat (HFD) and low fat (LFD) diet fed mice livers. We quantified 2447 proteins and 1339 phosphoproteins containing 1650 class I phosphosites, of which 669 phosphosites were significantly different between HFD and LFD mice livers. We detected alterations of proteins associated with cellular metabolic processes such as small molecule catabolic process, monocarboxylic acid, long- and medium-chain fatty acid, and ketone body metabolic processes, and peroxisome organization. We observed a significant downregulation of protein phosphorylation in HFD fed mice liver in general. Untargeted lipidomics identified upregulation of triacylglycerols, glycerolipids and ether glycerophosphocholines and downregulation of glycerophospholipids, such as lysoglycerophospholipids, as well as ceramides and acylcarnitines. Analysis of differentially regulated phosphosites revealed phosphorylation dependent deregulation of insulin signaling as well as lipogenic and lipolytic pathways during HFD induced obesity. Thus, this study reveals a molecular connection between decreased protein phosphorylation and lipolysis, as well as lipid-mediated signaling in diet-induced obesity.

Previous work has demonstrated that animals exhibit behavioral and physiological responses to dietary protein restriction, including that protein-restricted rodents respond at higher levels for a protein reinforcer than non-restricted rodents. The current study assessed the effect of dietary protein restriction on behavioral economic demand for protein. Demand for a casein solution was assessed by varying the number of responses required to obtain access to the solution and measuring the number of deliveries obtained at each response requirement. Body weights and food intake were measured regularly and home-cage preference assessments using casein and maltodextrin solution were used to probe preference at key time points. Protein-restricted mice exhibited lower rates of weight gain, increased food intake, increased preference for protein, and increased operant responding and demand for a protein solution relative to non-restricted mice. Additionally, it was found that the inclusion of saccharin in the casein solution obscured group differences in operant demand by elevating responding in the normal protein-fed mice. Further, when mice that were previously protein-restricted were fed a normal protein diet, demand for casein solution remained higher in those mice than in mice that had not been protein-restricted. These findings indicate that a history of protein restriction may lead to a persistent increased demand for protein.

Prostate cancer (PCa) growth is mediated by androgens via activation of androgen receptor (AR). Accordingly, androgen deprivation therapy (ADT) is the gold standard for the treatment of advanced PCa, but progression to castration-resistant PCa (CRPC) follows. Enzalutamide (ENZ) is an AR antagonist used for the management of CRPC. However, patients acquire resistance to the drug in a short period. Meanwhile, cholesterol is a precursor to androgen and its metabolism is dysregulated in PCa. In addition, cholesteryl ester (CE) accumulation aggravates tumor growth but its association with ENZ treatment has not been studied. Thus, we hypothesized that inhibition of CE formation by blockage of sterol-O-acyltransferase 1 (SOAT1) could enhance the response to ENZ. We found that SOAT1 mRNA is upregulated in clinical prostate tumors compared to normal/benign tissues in TCGA dataset. SOAT1 mRNA level was also highly correlated with AR expression in SU2CF/PCF cohorts and TCGA dataset, suggesting critical role of the cholesterol metabolism in prostate tumor progression and potential association to AR signaling pathway. We treated 22RV1 prostate cancer cells with ENZ in the presence or absence of SOAT1 inhibitor, avasimibe, and found the combination treatment effectively reduced the level of CEs compared to control, which accompanied inhibition of colony formation and cell proliferation. Combination index value was calculated and the relationship between the two drugs showed synergism. Furthermore, genetic knockdown of SOAT1 sensitized cells to ENZ treatment and also reduced the number of colonies formed. In TCGA dataset, patients who had previously undergone ADT were analyzed, and their Kaplan-Meier survival curve showed low SOAT1 expressing patients had a significantly longer progression-free survival rate than their counterpart, indicating that SOAT1 could act as a prognostic biomarker predicting PCa treatment outcome. Gene set enrichment analysis of patients with ADT history showed androgen response gen sets were enriched in high SOAT1 expressing PCa patient group. Inhibition of SOAT1 and the combination treatment did not change AR and ARV7 protein level, but downstream genes such as PSA were down regulated upon the combination treatment. In summary, our in vitro results showed blockage of SOAT1 enzyme sensitized PCa cells to ENZ treatment and analysis of PCa patient data suggested that SOAT1 gene expression has potential as a prognostic marker. Citation Format: Sora Q. Kim, Sagar Utturkar, Nadia M. Atallah, Kee-Hong Kim. A pharmacological inhibition of sterol O-acyltransferase 1improves response to enzalutamide in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5468.