SHetA2 is a heteroarotinoid that has shown selective inhibition of cancer cell growth and an induction of apoptosis without activation of nuclear retinoic acid receptors. In the rat study, SHetA2 was administered in 1% aqueous methylcellulose/0.2% Tween 80 by oral gavage at 0, 100, 500, and 2,000 mg/kg/day for 28 days. The high-dose administration induced decreased activity in male rats, decreased body-weight gains and food consumption, and changes in organ weights. The major metabolite of SHetA2 in rat plasma was monohydroxy SHetA2, which was considerably higher than the parent compound after oral and intravenous administration. Pharmacokinetic analysis showed extremely low (<1%) systemic bioavailability of SHetA2 for all doses tested. The dose of 2,000 mg/kg/day was considered as the lowest observed adverse effect level. The no observed adverse effect level (NOAEL) was 500 mg/kg/day. In the dog study, no toxicity of SHetA2 in 30% aqueous Solutol(®) HS 15 was observed in any tested dose groups (0, 100, 400, and 1,500 mg/kg/day). The major metabolite of SHetA2 in dog plasma was also monohydroxy SHetA2, which was equal to or lower than the parent compound after oral administration. SHetA2 levels in dog plasma were notably higher, when compared to levels in rat plasma. However, exposure was not dose proportional, as exemplified by a lack of proportional increase in maximum concentration or area under the plasma concentration-time curve with increasing dose. The NOAEL was not established and was considered to be above 1,500 mg/kg/day.

Ventilatory responses to isocapnic, progressive hypoxic rebreathing (HVR), in supine and sitting positions, lung ventilation and gas exchange while breathing air and during 5 min of breathing 11% O₂ in N₂ were studied in 12 healthy young (20–28 years), 5 old (57–73 years) male subjects, and in 7 male patients with Parkinson’s disease (PD) aged 55–67 years. The piecewise linear approximation technique was used for evaluation of the ventilatory response curves, which allowed a separate analysis of slopes during minor and severe hypoxia. It has been shown that body position affected HVR. In the range of P_ETO₂ from 60 to 35 mm Hg, the ventilatory response in the sitting position was higher than supine: in young persons by 43%, in healthy old persons by 76%, and in the PD patients by 211%. No significant differences in HVR to minor hypoxia (P_ETO₂ from 100 to 60 mm Hg) were found in the 3 groups. During severe hypoxia (P_ETO₂ from 60 to 35 mm Hg) the slope of minute ventilation versus O₂ was 4.6 (supine) and 2.6 (sitting) times greater in healthy old men than PD patients’ slopes. PD patients compared to old controls had 32% lower alveolar ventilation, 10% lower P_ETO₂ and 15% elevation of P_ETCO₂ while breathing air; similar differences were found while the patients were breathing 11% O₂. The reduced alveolar ventilation under severe hypoxia in patients with PD could not be attributed to mechanical restriction of lung function. We suggest that the discrepancy in HVR under minor and severe hypoxia results from dysfunction in chemoreception associated with Parkinsonism.

The effects of C60FAS (50 and 500 μg/kg) supplementation, in a normal physiological state and after restraint stress exposure, on prooxidant/antioxidant balance in rat tissues were explored and compared with the effects of the known exogenous antioxidant N-acetylcysteine. Oxidative stress biomarkers (ROS, O2·−, H2O2, and lipid peroxidation) and indices of antioxidant status (MnSOD, catalase, GPx, GST, γ-GCL, GR activities, and GSH level) were measured in the brain and the heart. In addition, protein expression of Nrf2 in the nuclear and cytosol fractions as well as the protein level of antiradical enzyme MnSOD and GSH-related enzymes γ-GCLC, GPx, and GSTP as downstream targets of Nrf2 was evaluated by western blot analysis. Under a stress condition, C60FAS attenuates ROS generation and O2·− and H2O2 releases and thus decreases lipid peroxidation as well as increases rat tissue antioxidant capacity. We have shown that C60FAS supplementation has dose-dependent and tissue-specific effects. C60FAS strengthened the antiradical defense through the upregulation of MnSOD in brain cells and maintained MnSOD protein content at the control level in the myocardium. Moreover, C60FAS enhanced the GSH level and the activity/protein expression of GSH-related enzymes. Correlation of these changes with Nrf2 protein content suggests that under stress exposure, along with other mechanisms, the Nrf2/ARE-antioxidant pathway may be involved in regulation of glutathione homeostasis. In our study, in an in vivo model, when C60FAS (50 and 500 μg/kg) was applied alone, no significant changes in Nrf2 protein expression as well as in activity/protein levels of MnSOD and GSH-related enzymes in both tissues types were observed. All these facts allow us to assume that in the in vivo model, C60FAS affects on the brain and heart endogenous antioxidative statuses only during the oxidative stress condition.

BackgroundAntarctica is a unique place to study the health condition under the influence of environmental factors on the organism in pure form. Since the very beginning of the scientific presence of Ukraine in the Antarctic, biomedical research has been developed for the monitoring of individual biomarkers of winterers and medical accompaniment in Antarctic expeditions. The aim of the study was to analyze and discuss the retrospective data of long-term monitoring and observations in Ukrainian Antarctica station “Akademik Vernadsky,” providing multi-scale biomedical information with regard to conditions of a perfect isolation from technological and social influences and under extreme environmental factors.MethodsMedical and biological studies have been performed with the participation of all 20 Ukrainian wintering expeditions. We surveyed 200 males aged 20–60 years (mean age 37 years). Extensive medical examinations were carried out before the expedition, during the selection of candidates, and after returning, and particular functions were monitored during the entire stay in Antarctica. The medical records were analyzed to study the reaction of the human organism on phenomena like “Antarctic syndrome,” dysadaptation, anxiety, desynchronosis, photoperiodism, influence of climatic and meteofactors like “Schumann resonance,” infrasound, “ozone hole,” and “sterile” environment; important aspects of its role on human health were precisely studied and discussed.ResultsThe examinations showed the multi-level symptoms of the processes of dysregulation and dysadaptation, as functional tension in the sympathetic-adrenal system rights, especially during urgent adaptation to the Antarctic (1-month stay at the station) and, to a lesser extent, after returning from an expedition to Kyiv. At the initial, adaptation to the conditions of the Antarctic levels of urinary catecholamines (epinephrine, norepinephrine, dopamine, DOPA) increased compared with the start of the expedition (23.2 ± 4.3 and 53.3 ± 5 2 mmol/l, p < 0.001; 67.1 ± 12.3 and 138.3 ± 16.9 mmol/l, p < 0.01; 1749.6 ± 476.5 vs 7094.6 ± 918.3 mmol/l, p < 0.001; 129.6 ± 12.3 and 349.9 ± 40.6 mmol/l, p < 0.001, respectively). In the blood serum of 100 % of the expedition, we found an increase of oxidative stress markers—the level of TBARS increased by 41.2 %, i.e., the activation of free radical peroxidation. Thus, in 80 % of the participants, we observed a reduction in the activity of the SOD antiradical enzyme vs 58 % in the controls. Changes in brain electrical activity after a long stay at the Antarctic stations showed increasing delta rhythms, signs of CNS protective inhibition, likely due to hypoxia. We found changes in the concentrations of microelements (iron, copper, zinc, etc.) in the blood of winterers after the expedition. The polychrome-adaptive method of correcting the changes of the psycho-emotional state in a monochrome Antarctic environment was successfully applied.ConclusionsThe preliminary results of the retrospective study and our own observations of ...