Deciphering the Puzzle of Hypobaric Hypoxia Proteomics Prophylaxis and Modelling Approach

Abstract

Hypoxia, particularly hypobaric hypoxia, is a multifaceted entity which includes certain molecular, patho-physiological and biochemical aspects. Any single aspect in itself cannot help us elucidate hypobaric hypoxia in its entirety. We observed three crucial lacunae within the existing literature. These include a lack of high-throughput investigations into redox PTMs, particularly NO-based PTMs; a prophylactic supplement with proven efficacy and safety which doesn’t involve medical supervision and is not contraindicated in hepatic, renal and cardiac insufficiencies; and a clinically validated rodent model of HAPE without any genetic/pharmacological manipulations. In the present study, we present an antagonistic interplay between nitrosylation and carbonylation which shows an additional NO-based network that is active in acclimatised individuals. Then we present a micronised aqueous suspension of silymarin which is efficacious at low doses in providing antioxidant, anti-inflammatory and hypoxia-adaptive vascular responses in addition to being a free radical quencher itself. Silymarin has an excellent safety and efficacy profile in humans. Finally, we create a SD rat model of HAPE which was used to reverse-translate a previously known HAPE marker in humans (SULT1A1) and elucidate the synergistic occurrence of HAPE and inflammation cascades. This is the first radiologically validated rodent HAPE model. In conclusion, we were able to elucidate the molecular, biochemical and patho-physiological aspects of hypobaric hypoxia which were left out by previous studies.