The immune system as a chronotoxicity target of the anticancer mTOR inhibitor everolimus

The circadian timing system controls many biological functions in mammals including xenobiotic metabolism, detoxification, cell proliferation, apoptosis and immune functions. Everolimus is a mammalian target of rapamycin inhibitor, whose immunosuppressant properties are both desired in transplant patients and unwanted in cancer patients, where it is indicated for its antiproliferative efficacy. Here we sought whether everolimus circadian timing would predictably modify its immunosuppressive effects so as to optimize this drug through timing. C57BL/6J mice were synchronized with light-dark 12h:12h, with L onset at Zeitgeber Time (ZT) 0. Everolimus was administered orally to male (5 mg/kg/day) and female mice (15 mg/kg/day) at ZT1, during early rest span or at ZT13, during early activity span for 4 weeks. Body weight loss, as well as hematological, immunological and biochemical toxicities, were determined. Spleen and thymus were examined histologically. Everolimus toxicity was less severe following dosing at ZT13, as compared to ZT1, as shown with least body weight inhibition in both genders; least reductions in thymus weight both in males (p < 0.01) and females (p < 0.001), least reduction in female spleen weight (p < 0.05), and less severe thymic medullar atrophy both in males (p < 0.001) and females (p < 0.001). The mean circulating counts in total leukocytes, total lymphocytes, T-helper and B lymphocytes displayed minor and non-significant changes following dosing at ZT13, while they were decreased by 56.9% (p < 0.01), 45.5% (p < 0.01), 43.1% (p < 0.05) and 48.7% (p < 0.01) after everolimus at ZT1, respectively, in only male mice. Chronotherapy of everolimus is an effective way to increase the general tolerability and decrease toxicity on the immune system.     

Heliotropium thermophilum,an extreme heat tolerant species,promises plants about adaptation to high soil temperature conditions

To understand high temperature tolerance, Heliotropium thermophilum, a flowering plant thriving in a geothermal field with a soil temperature ranging between 55 and 65 °C, was grown in controlled laboratory conditions and two different soil temperatures were applied to the plants. One of them was the control group (CT 25 ± 3 °C) and the other was the high temperature group (HT 60 ± 4 °C). Water potential, dry weight, cell membrane injury (CMI), lipid peroxidation, hydrogen peroxide, chlorophylls, carotenoids, flavonoids, anthocyanins, proline and total soluble sugar contents were measured. Contents of total soluble sugars, phenolics, flavonoids, anthocyanins, proline were found to be higher in HT group than CT while CMI was opposite. Moreover, no difference was determined in water potential, dry weight, lipid peroxidation, total chlorophyll and carotenoids between CT and HT. H. thermophilum plants adapted to high temperature under laboratory conditions through changing membrane lipid saturation, accumulating osmotically active compounds to save water or increase its uptake and inducing antioxidants such as phenolic compounds to keep reactive oxygen species under control. In conclusion, this study showed that H. thermophilum plant was highly resistant to high soil temperature under optimized laboratory conditions. Moreover, a plant that can withstand 60 °C for a long period of time up to 60 days under laboratory conditions was reported for the first time.