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  • On the other hand our study permits to

    2023-01-29

    On the other hand, our study permits to draw general conclusions about the complex functional pattern of C4HT, C8HT and C12HT, in comparison with the parent molecule HT and two reference compounds like Trolox and vitamin E. Table 1 summarizes the results obtained in the present investigation (for the sake of completeness, Table 1 includes data referring to C18HT but it is should be kept in mind that some of such values should be considered cautiously). C.a.c. assessments permit to observe an inverse relation between the length of the acyl alkyl chain and solubility of HT esters as monomer, including C4HT and C18HT, by extrapolation (Fig. 2b). The found linearity is typical in compounds often displaying regular surfactant properties. The latter feature (surface activity) is thought to be strictly related to the efficacy of an antioxidant in oil-in-water emulsion. Some authors sustain that for improving the ability to counteract lipid oxidation in emulsions and other dispersed lipid systems, an antioxidant should also be an effective surfactant [39]. Another formulated PRIMA-1MET for the drop of bioactivity achieved in derivatives having acyl chain length>C12 is the entrapment into the plasma membrane. The similarity between the liposomal and cellular membranes makes liposomes a very useful tool to investigate how significant the antioxidant-membrane interactions are for antioxidant activity. DLS data (Fig. S1) confirmed a not disruptive interaction between POPC membranes and antioxidants, as in their presence liposomes do not self-aggregate or break. Binding studies (Fig. 3, Fig. 4) revealed that C8HT, C12HT and C18HT have all an excellent affinity for the liposome membrane, as expected, whereas C4HT does not. However, if these compounds are added to pre-formed liposomes, C18HT insertion is strongly reduced, we claim for kinetic reasons. These observations explain the changes in Laurdan GP and the better activity in DPH-based assay for C8HT and C12HT. In aqueous media, antioxidant activity depends only on the capacity of the substance to scavenge the peroxyl radicals, thus avoiding oxidation of the probe. In these conditions, C4HT, C8HT and C12HT display a similar activity, whereas C18HT activity could not be detected, probably because of the mentioned solubility problems. The analogous tests in the liposome lumen (both conventional and giant liposomes) outlined that the differences of action, depending on the chain length, can be ascribed to a combination of factors. First of all, data tell us that the butyrate derivative, in contrast to the other long-chain HT esters, is well able to cross the phospholipid membrane by passive diffusion. Indeed C4HT proved to be the most efficient in preventing the intravesicle probe oxidation, notwithstanding with the fact that it has been externally added to pre-formed liposomes. Because C4HT, C8HT and C12HT have similar antioxidant activity with respect to bulk H2DCF oxidation, it follows that the differences observed in liposome studies derive from the different capacity of reaching the liposome core and act as local anti-oxidant shielding agent. C4HT permeates the liposome membrane. In fact it performs well in the case of H2DCF-containing vesicles even if no membrane-bound C4HT could be detected in binding assay. Yet its intra-vesicle antioxidant activity shows that C4HT enters the vesicle. Moreover, the absence of bound C4HT in the experiments of Section 2.2.1 shows that after its passive inward diffusion, C4HT is also released by a passive outward diffusion during chromatographic separation (so that no C4HT could be found associated to liposome fractions). In comparison, the other longer-chain esters remains anchored to the membrane and can be found associated to liposomes after chromatography. With respect to the kind of experiments done in this study, which simulate in vitro assays in cultured cells, C8HT shows the best performance when membrane-related functions are considered. It is capable of being partly soluble in water, thus it can reach the membrane as monomer or as small aggregates, and insert therein (maybe reversibly). These features derive from a good compromise between the amphiphilic properties of HT esters.