Adaptive Membrane Fluidity Modulation: A Feedback Regulated Homeostatic System and Target for Pharmacological Intervention

Abstract

Background/Aim: Alterations of plasma membrane fluidity are characteristic of many diseases but the intentional modulation of membrane fluidity with drugs has been less studied. We examined the therapeutic potential of the membrane fluidizer diethyl azelate (DEA) and related azelates. Materials and Methods: The effects of azelates on plasma membrane fluidity and cell signaling were examined in primary human and murine cells and in vivo. Endpoints were queried using single target and multiplexed immunoassays. Results: Unique membrane-fluidizing properties and biomarker signatures suggest that azelates are not prodrugs. DEA decreased cytokine signaling from pattern recognition receptors in human dendritic cells, disabled membrane attack of cholera toxin in vitro, and prevented immunosuppression by anthrax lethal toxin in vitro and in vivo. In the murine sepsis model, DEA increased survival and reduced organ damage. Conclusion: Azelates represent a new class of drugs, membrane active immunomodulators, which target an innate homeostatic mechanism, adaptive membrane fluidity modulation.

Azelaic Acid Esters as Pluripotent Immunomodulatory Molecules: Nutritional Supplements or Drugs

“…We have examined DEA metabolism in hepatocytes from representative animal models in a side-by-side comparison with human hepatocytes. In the past, we have shown that DEA was non-toxic up to concentrations as high as 25% v/v in different types of normal human cells [6]. In the present studies in mammalian hepatocytes, the concentrations of DEA corresponded to the anticipated liver levels of the ester following a single oral or an intravenous dose in vivo.…”

“…Building upon our earlier findings that demonstrated lack of DEA mutagenicity using in silico and in vitro assays [6], we have further expanded the study to include a panel of Samonella strains commonly used in testing developmental drugs [32]. The concentrations of DEA spanned a broad range, corresponding to approximately 1000% of the intended oral dose.…”

“…AZA modulates the innate immune responses in human skin [4,5]. The immunomodulatory role of the azelates, and especially diethyl azelate (DEA), has been discovered only recently [6,7]. These findings suggest highly conserved functions of AZA and azelates in multicellular organisms.…”

“…However, the azelates have been little explored as drugs. We have identified the azelates as representatives of a new class of drugs and discovered a number of potential applications of DEA and other azelates in treating diverse human pathologies [6,7,21].…”

“…In our past studies, we have found that DEA is not mutagenic using in silico and in vitro assays, and it is not cytotoxic in various types of primary normal human cells [6]. Importantly, we have found that oral DEA has displayed an inverse U-shape dose response effect with an optimum around 1 mg/kg [21][22][23].…”