Abstract
Dihydrochalcones, phlorizin (PZ) and its aglycone phloretin (PT), have evidenced immunomodulatory effects through several mechanisms. However, the differential metabolic signatures that lead to these properties are largely unknown. Since macrophages play an important role in the immune response, our study aimed to characterise human THP-1 macrophages under PZ and PT exposure. A multiplatform-based untargeted metabolomics approach was used to reveal metabolites associated with the anti-inflammatory mechanisms triggered by the dihydrochalcones in LPS-stimulated macrophages, for the first time. Results showed differential phenotypic response in macrophages for all treatments. Dihydrochalcone treatment in LPS-stimulated macrophages mimics the response under normal conditions, suggesting inhibition of LPS response. Antagonistic effects of dihydrochalcones against LPS was mainly observed in glycerophospholipid and sphingolipid metabolism besides promoting amino acid biosynthesis. Moreover, PT showed greater metabolic activity than PZ. Overall, the findings of this study yielded knowledge about the mechanisms of action PZ and PT at metabolic level in modulating inflammatory response in human cells.
Highlights
Published: 3 February 2021Phlorizin (PZ) and its aglycone phloretin (PT), the major dihydrochalcone flavonoids found in apples, have been shown to exert beneficial effects on the human health such as antioxidant potential [1], anti-cancer effects [2,3] and immunomodulatory activities both in vitro and in vivo [4]
To evaluate the immunomodulatory role of dihydrochalcones through metabolomics, Tetradecanoylphorbol 13-acetate (TPA)-differentiated human TPH-1 macrophages were cultured with dihydrochalcones standards
This study provides an untargeted multiplatform metabolite profiling approach to understand metabolic effects promoted by phlorizin and phloretin, under normal and inflammatory conditions, in human macrophage-like THP-1 cells by LC-QTOF-MS and GC-MS
Summary
Phlorizin (PZ) and its aglycone phloretin (PT), the major dihydrochalcone flavonoids found in apples, have been shown to exert beneficial effects on the human health such as antioxidant potential [1], anti-cancer effects [2,3] and immunomodulatory activities both in vitro and in vivo [4]. Since macrophages are the most critical cells in initiation, maintenance, and resolution of inflammation [5], dihydrochalcone effects on these cells have been evaluated They are a heterogeneous population of cells with high ability to acquire distinct functional phenotypes in response to different environmental changes and stimuli [6]. Activated macrophages are deactivated by anti-inflammatory cytokines such as interleukin 10 (IL-10) and transforming growth factor beta (TGF-β); and cytokine antagonists that are mainly produced by macrophages. Macrophages participate in an autoregulatory process necessary for maintaining the tissue homeostasis [5]
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