In ring more effectively than the TPP-14-ISA as suggested by ESEEM data. Elucidation of these intermolecular stabilization mechanisms of cyt c identified TPP-6-ISA as an effective inhibitor of the peroxidase function of CL/cyt c complexes with a significant anti-apoptotic potential realized in MECs exposed to ionizing irradiation. These experimental findings were further detailed and confirmed by the computational analysis. All atom simulations suggested that the ISA moiety, rather than the TPP group, was the major contributor to the binding free energy of TPP-ISA. These hydrophobic interactions of TPP-n-ISA with heme iron are important in regulation of the ratios of high spin/low spin forms with different symmetry. Imidazole substitution closer to the carboxyl end of the fatty acid chain resulted in burial of a larger hydrophobic surface and produced derivatives that more effectively interacted with cyt c/CL complex. The higher antiperoxidase potency of TPP-6-ISA vs TPP-14-ISA was also supported by the computational analysis which revealed that TPP-6-ISA and TPP-8-ISA, with higher buried hydrophobic surface area, were better ligands of TOCL/cyt c when compared to TPP-12-ISA or TPP-14ISA. These computational interpretations are consistent with previously published EPR data demonstrating the importance of hydrophobic interactions in the lipid-induced modulation of cyt c spin states [37]. Addition of more hydrophobic lipids with longer acyl chains increased the content of high spin species of cyt c. On the other hand, addition of zwitterionic short chain lipids such as dibutyryl PC (C4:0) and didecanoyl PC (C10:0) did not affect the spin state of cyt c. Massive apoptotic cell death resulting in the disruption of essential barriers and tissue and organ failure has been associated with the major pathogenic mechanisms of acute injury. This necessitates the design and development of new anti-apoptotic drugs. Aiming at CL oxidation as a drug target may be particularly promising as it allows for a therapeutic window of several hours from the moment of exposure yet prevents the release of proapoptotic factors from mitochondria into the cytosol an event designating the point-of-noreturn in apoptosis [3]. Our previous work documented the validity of this approach in acute brain injury (Ji et al., 2012) and acute radiation injury [6]. The effectiveness of TPP-nISA analogues, particularly TPP-6-ISA, as inhibitors of radiation induced programmed cell death may be important for the development of radiomitigative modalities. Indeed, the reality of intentional human exposure to ionizing radiation during radiotherapy and risks of unintended exposure from nuclear accidents, unavoidable occupational environments, as well as exposures during space exploration or potential terroristic attacks necessitates design and development of effective protective/mitigative modalities.Phenylbutyrate This requires profound understanding of the mechanisms of radiation-induced damage.D-chiro-Inositol High doses of irradiation induce acute radiation syndrome associated with massive cell loss in radiosensitive organs, believed to be mostly due to triggering of intrinsic, mitochondria-mediated, apoptosis [60].PMID:28322188 This emphasizes the importance of the identification of TPP-6-ISA as a candidate drug with optimized radiomitigative potency.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptFree Radic Biol Med. Author manuscript; available in PMC 2015 June 01.Jiang et al.PageSupplementary Mate.
